Qualitative structure-metabolism relationships in the...
39
Introduction e carbamate moiety plays a noteworthy role in medici- nal chemistry, being found in drugs as well as in prod- rugs (Testa and Mayer, 2003). Many of the carbamates in the field of medicinal chemistry are marketed drugs or drug candidates in preclinical or clinical trials. For such drugs, the carbamate group is an important feature of the molecule, sometimes being endowed with a major role in drug-target interaction (e.g., acetylcholine inhibitors). In this case, metabolic hydrolysis may lead to an inactive metabolite and thus be a reaction of inactivation (e.g., felbamate) or yield an active metabolite that comple- ments and prolongs the activity of the parent drug (e.g., loratadine). In the case of prodrugs, hydrolysis yields the activated metabolite and is thus a reaction of bioactivation, as exemplified by bambuterol, the prodrug of terbutaline (Ettmayer et al, 2004; Raito et al, 2008; Testa, 2007, 2009; Testa and Krämer, 2009). But, whether drug or prodrug, the rate and extent of hydrolysis of carbamates is critical for the duration and intensity of their pharmacological activity. Fast hydrolysis of carbamate-bearing drugs may result in weak and/or short activity. e opposite is often true for carbamate-based prodrugs, whose hydrolysis to liberate an active amine or phenol must be extensive and of adequate velocity to obtain the expected level and time profile of activity. e aims of the present review were 1) to compile as many cases of metabolic hydrolysis of bioactive carbamates as possible and 2) to extract qualitative structure-metabolism relations from the compiled data, bearing in mind the great diversity of biological condi- tions under which such data were obtained. Data collection and classification An extensive literature search was performed to identify carbamate-bearing molecules for which chemical or met- abolic stability data were available, with a special focus on reactions of hydrolysis having the carbamate moiety as Drug Metabolism Reviews, 2010; 42(4): 551–589 Address for Correspondence: Federica Vacondio, Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G.P. Usberti 27/a, I-43100 Parma, Italy; Fax: (+39) 0521 905006; E-mail: [email protected] REVIEW ARTICLE Qualitative structure-metabolism relationships in the hydrolysis of carbamates Federica Vacondio 1 , Claudia Silva 1 , Marco Mor 1 , and Bernard Testa 2 1 Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy, and 2 Department of Pharmacy, University Hospital Centre (CHUV), Lausanne, Switzerland Abstract The aims of this review were 1) to compile a large number of reliable literature data on the metabolic hydrolysis of medicinal carbamates and 2) to extract from such data a qualitative relation between molecular structure and lability to metabolic hydrolysis. The compounds were classified according to the nature of their substituents (R 3 OCONR 1 R 2 ), and a metabolic lability score was calculated for each class. A trend emerged, such that the metabolic lability of carbamates decreased (i.e., their metabolic stability increased), in the follow- ing series: Aryl-OCO-NHAlkyl >> Alkyl-OCO-NHAlkyl ∼ Alkyl-OCO-N(Alkyl) 2 ≥ Alkyl-OCO-N(endocyclic) ≥ Aryl- OCO-N(Alkyl) 2 ∼ Aryl-OCO-N(endocyclic) ≥ Alkyl-OCO-NHAryl ∼ Alkyl-OCO-NHAcyl >> Alkyl-OCO-NH 2 > Cyclic carbamates. This trend should prove useful in the design of carbamates as drugs or prodrugs. Keywords: Carbamates; structure-property relationships (SPR); hydrolysis; metabolic stability; drug metabolism (Received 20 November 2009; revised 05 February 2010; accepted 03 March 2010) ISSN 0360-2532 print/ISSN 1097-9883 online © 2010 Informa Healthcare USA, Inc. DOI: 10.3109/03602531003745960 http://www.informahealthcare.com/dmr Drug Metabolism Reviews Downloaded from informahealthcare.com by Cantonale et Universitaire on 09/30/10 For personal use only.
Transcript of Qualitative structure-metabolism relationships in the...
Introduction
The carbamate moiety plays a noteworthy role in medici-nal chemistry, being found in drugs as well as in prod-rugs (Testa and Mayer, 2003). Many of the carbamates in the field of medicinal chemistry are marketed drugs or drug candidates in preclinical or clinical trials. For such drugs, the carbamate group is an important feature of the molecule, sometimes being endowed with a major role in drug-target interaction (e.g., acetylcholine inhibitors). In this case, metabolic hydrolysis may lead to an inactive metabolite and thus be a reaction of inactivation (e.g., felbamate) or yield an active metabolite that comple-ments and prolongs the activity of the parent drug (e.g., loratadine).
In the case of prodrugs, hydrolysis yields the activated metabolite and is thus a reaction of bioactivation, as exemplified by bambuterol, the prodrug of terbutaline (Ettmayer et al, 2004; Raito et al, 2008; Testa, 2007, 2009; Testa and Krämer, 2009). But, whether drug or prodrug, the rate and extent of hydrolysis of carbamates is critical
for the duration and intensity of their pharmacological activity. Fast hydrolysis of carbamate-bearing drugs may result in weak and/or short activity. The opposite is often true for carbamate-based prodrugs, whose hydrolysis to liberate an active amine or phenol must be extensive and of adequate velocity to obtain the expected level and time profile of activity.
The aims of the present review were 1) to compile as many cases of metabolic hydrolysis of bioactive carbamates as possible and 2) to extract qualitative structure-metabolism relations from the compiled data, bearing in mind the great diversity of biological condi-tions under which such data were obtained.
Data collection and classification
An extensive literature search was performed to identify carbamate-bearing molecules for which chemical or met-abolic stability data were available, with a special focus on reactions of hydrolysis having the carbamate moiety as
Drug Metabolism ReviewsDrug Metabolism Reviews, 2010; 42(4): 551–589
2010
42
4
551
589
Address for Correspondence: Federica Vacondio, Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G.P. Usberti 27/a, I-43100 Parma, Italy; Fax: (+39) 0521 905006; E-mail: [email protected]
20 November 2009
05 February 2010
03 March 2010
0360-2532
1097-9883
© 2010 Informa Healthcare USA, Inc.
10.3109/03602531003745960
R E V I E W A R T I C L E
Qualitative structure-metabolism relationships in the hydrolysis of carbamates
Federica Vacondio1, Claudia Silva1, Marco Mor1, and Bernard Testa2
1Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy, and 2Department of Pharmacy, University Hospital Centre (CHUV), Lausanne, Switzerland
AbstractThe aims of this review were 1) to compile a large number of reliable literature data on the metabolic hydrolysis of medicinal carbamates and 2) to extract from such data a qualitative relation between molecular structure and lability to metabolic hydrolysis. The compounds were classified according to the nature of their substituents (R3OCONR1R2), and a metabolic lability score was calculated for each class. A trend emerged, such that the metabolic lability of carbamates decreased (i.e., their metabolic stability increased), in the follow-ing series: Aryl-OCO-NHAlkyl >> Alkyl-OCO-NHAlkyl ∼ Alkyl-OCO-N(Alkyl)
2 ≥ Alkyl-OCO-N(endocyclic) ≥ Aryl-
OCO-N(Alkyl)2 ∼ Aryl-OCO-N(endocyclic) ≥ Alkyl-OCO-NHAryl ∼ Alkyl-OCO-NHAcyl >> Alkyl-OCO-NH
2 > Cyclic
carbamates. This trend should prove useful in the design of carbamates as drugs or prodrugs.
Keywords: Carbamates; structure-property relationships (SPR); hydrolysis; metabolic stability; drug metabolism
DMR
475118
(Received 20 November 2009; revised 05 February 2010; accepted 03 March 2010)
ISSN 0360-2532 print/ISSN 1097-9883 online © 2010 Informa Healthcare USA, Inc.DOI: 10.3109/03602531003745960 http://www.informahealthcare.com/dmr
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552 F. Vacondio et al.
a target site (i.e., the “soft spot,” in the current parlance). A first decision was to limit the search of experimental data to carbamates of pharmaceutical interest. Carbamates acting as pesticides or herbicides were not considered and would have required a separate analysis.
The search began either by entering keywords in public or commercial databases (e.g., Current Contents, Medline, PubMed, ScienceDirect, etc.) or directly on the websites of xenobiotic metabolism and medicinal chemistry journals (e.g., British Journal of Pharmacology, Current Drug Metabolism, Drug Metabolism and Disposition, Drug Metabolism Reviews, Journal of Medicinal Chemistry, Journal of Pharmaceutical Sciences, Journal of Pharmacology and Experimental Therapeutics, Pharmaceutical Research, Xenobiotica, etc.) or by employ-ing two-dimensional (2D) structure-based search engines (e.g., Beilstein Commander, SciFinder Scholar). After identification of the hits, the search was further deepened by the subsequent reading and analysis of reference arti-cles and of the most relevant information within.
The classification of carbamates used in this article was based on strictly structural criteria. The primary subdivision separated O-alkyl (Tables 1–4) and O-aryl carbamates (Tables 5–7). Cyclic carbamates were clas-sified separately (Table 8). The secondary subdivision was based on the number and nature of substituents on the carbamate nitrogen, (i.e., unsubstituted nitrogen) (Table 1), monosubstituted nitrogen (Tables 2, 3, 5, and 7), and disubstituted nitrogen, including carbamates with endocyclic N-atoms (Tables 2, 4, 6, and 7).
Whenever available, the biological and accompanying data compiled in Tables 1–8 include 1) the pharmaco-logical class of the carbamate substrate (column II), 2) its chemical structure (column III), 3) the chemical struc-ture of its metabolites derived from carbamate cleavage (column IV), and 5) metabolic reactions (including conjugations) directly competitive with carbamate cleav-age (column V). This last piece of information is meant to help readers view the reaction of interest in a global metabolic context and grasp its relative importance. Useful indications on experimental conditions are also provided (column VI), including animal species, in vitro versus in vivo conditions, the type of in vitro models (i.e., S9000 liver fraction, microsomes, cytosol, cultured cells, and perfused organs), or the route of administration.
The analytical methods used are summarized in col-umn VI, together with the relevant reference, a useful information to estimate the quality of metabolic data. Interestingly, this information reveals the evolution of analytical methods over the years and decades, an issue beyond the scope of this review.
The last column (column VII) summarizes hydrolysis data obtained in buffers (i.e., chemical hydrolysis; first row in box), in in vitro bioassays (second row in box), and in in vivo (third row in box). The chemical and
in vitro results are reported with three score levels, from “0” [null to low extent (a few %) of hydrolysis] to “+” [low to medium (t
1/2 up to about 1 day)] to “++” [medium to high
(t1/2
about 1 hour or less)]. The third row refers instead to in vivo metabolism, and, in this case, a simple yes/no answer is reported: yes = metabolite due to carbamate cleavage observed; no = ≤5% of total metabolism could be attributed to hydrolytic cleavage. This was mainly due to the impossibility of evaluating the relative weight of the hydrolytic pathway in the whole scenario of in vivo hydrolytic and oxidative biotransformations. The foot-notes in Table 1 explain abbreviations. Supplementary material complementing Tables 1–8 is in Tables 10–35.
Comments on Tables 1–8
The first question that arises in any literature review of this type calls for a simple yes/no answer: Is this spe-cific carbamate a substrate for hydrolysis? Column IV shows whether one or more metabolites resulting from hydrolytic cleavage are known or not. The comment “not reported” indicates that no relevant information was found in the literature. However, such a lack of informa-tion is ambiguous, since the type and quality of data has to be taken into consideration. Indeed, the investigators of the study might not have searched for products of hydrolysis, their focus having been on metabolic oxida-tion, or may have used unadapted biological protocols or analytical techniques. Despite these limitations, we have attempted to present the reader with a simplified score (column VII), representing the relative weight of hydrolytic metabolism, compared to other metabolic pathways.
In broad terms, it can be seen that the carbamate group is widely present in drugs, drug candidates, and prodrugs. In fact, many of the retrieved hits are marketed drugs or candidates in clinical trials or under preclinical development. For these molecules, the carbamate group either represents an important structural motif or even has a direct role in drug-target interaction.
Table 1 features O-alkylcarbamates that have an unsubstituted nitrogen, most of which are known drugs. For many of these compounds, in vitro results were rare, while metabolic hydrolysis represented only a minor pathway of in vivo biotransformation. Thus, the muscle relaxant methocarbamol (A.1.2) was not hydrolyzed in vivo (Campbell et al., 1961). Its close analog, chlorphe-nesin carbamate (A.1.3), was predominantly metabo-lized in rats and humans by direct conjugation of the unchanged drug, with only a modest fraction of the dose being recovered in urine as p-chlorophenylacetic acid (formed by hydrolysis, followed by alcohol deshydro-genation) (Buhler, 1964). Decarbamoylated metabolites of capravirine (A.1.8) were observed only in dogs (Bu
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Hydrolysis of carbamates: qualitative structure-metabolism relationships 553Ta
ble
1. Th
e m
etab
olic
hyd
roly
sis
of O
-alk
ylca
rbam
ates
(R
3 = A
lkyl
; R1 =
R2 =
H).
NO
OR3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.1
.1
O-(
n-a
lkyl
) ca
r-b
amat
es (
R =
Et,
B
u, H
exyl
& O
ctyl
)
OR
NH2
ON
one
rep
orte
d• (ω
−1)
-hyd
roxy
lati
on• Sa
rgen
t et a
l., 1
982a
(R
m-
Viv
o-P
O+
IV)
(LSC
; TLC
)• Sa
rgen
t et a
l., 1
982b
(R
m-V
ivo-
IP; R
-Hep
atoc
ytes
) (T
LC; M
S)
NR
e
0 (n
= 4
)f
Yesg
A.1
.2
Met
hoc
arb
amol
Mu
scle
rel
axan
tOCH3 O
OH
ONH2
ON
one
rep
orte
d• Dea
lkylation of m
ethox
y
grou
p• Hyd
roxylation
of p
hen
yl ring
• B
ruce
et a
l., 1
971
(H+
D+
R-
vivo
-PO
) (T
LC; L
SC; I
R; U
V;
NM
R)
• C
amp
bel
l et a
l., 1
961
(H+
D-
vivo
-PO
) (L
SC)
• M
uir
et a
l., 1
984
(Hor
se-
Viv
o-IV
) (H
PLC
-UV
)
NR
NR
No
A.1
.3
Ch
lorp
hen
esin
ca
rbam
ate
Mu
scle
rel
axan
t
O
OHO
NH2
O
Cl
OOH
COOH
Cl
• Glucu
ronidation
• B
uh
ler
1964
, 196
5 (H
+R
m-
Viv
o-P
O)
(Pap
er C
; LSC
)• B
uh
ler
et a
l., 1
966
(D-V
ivo-
P
O)
(Pap
er C
; LSC
)• B
uh
ler
and
Har
poo
tlia
n, 1
967
(Rm
-Viv
o-P
O; R
-L-M
) (T
LC;
Pap
er C
);• E
del
son
et a
l., 1
969
(Rm
+D
m-
Viv
o-P
O+
IP)
(TLC
; LSC
);• K
aise
r an
d S
haw
, 197
4 (H
-Viv
o-P
O)
(GC
)
NR
NR
Yes
A.1
.4
Car
isb
amat
e
An
tiep
ilep
tic
Cl
O
O
NH
2
OH
Cl
OH
OH
• O-glucu
ronidation
• Su
lfon
ation
• Chiral in
version at a
lcoh
ol
fun
ctio
n• Aromatic hyd
roxylation
• M
amid
i et a
l., 2
007
(R+
Mou
se+
Rab
bit
+D
-Viv
o-
PO
) (H
PLC
-MS;
HP
LC-R
AM
; N
MR
)• M
ann
ens
et a
l., 2
007
(H-V
ivo-
PO
) (H
PLC
-MS;
H
PLC
-RA
M)
NR
NR
Yes
A.1
.5
Ron
idaz
ole
An
tip
aras
itic
ag
ent
N
N CH3
O2N
O
O
NH2
N
N CH3
O2N
OH
• Exten
sive
ring scission
to
pro
du
ce N
-met
hyl
glyc
ol-
am
ide
• R
osen
blu
m e
t al.,
197
2
(Tu
rkey
-Viv
o-P
O)
(LSC
TLC
)N
R
NR
Yes
Tab
le 1
. co
nti
nu
ed o
n n
ext p
age
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No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.1
.6
Eth
inam
ate
Hyp
not
ic
CO
O NH2
HC
CO
2• Hyd
roxylation
of c
yclohex
yl
rin
g.• B
illin
gs e
t al.,
197
7 (R
-hep
atoc
yte)
(G
C-M
S)• K
leb
er e
t al.,
197
7 (H
-Viv
o-
PO
) (G
C-M
S)• M
cMah
on, 1
958
(R-V
ivo-
IV)
(Pap
er C
; LSC
)• Pa
rli e
t al.,
197
2 (R
-Viv
o-IP
; D
-Viv
o-IV
; R-L
-M)
(GC
)
NR
0 No
A.1
.7
Cef
oxit
in
Ch
emot
her
a-p
euti
c ag
ent
S
NO
O
NH2NaO
O
ONH
O
S
H3C
O
S
NHO
NaO
O
ONH
O
S
H3C
O
• Dea
cetylation
• B
rum
fitt
et a
l., 1
974
(H-V
ivo-
IM+
IV)
(dis
k-p
late
met
hod
)• B
uh
s et
al.,
197
4 (H
-Viv
o-IV
+IP
) (H
PLC
-UV
)
NR
NR
No
A.1
.8
Cap
ravi
rin
e
Non
-nu
cleo
sid
e re
vers
e-
tran
scri
pta
se
inh
ibit
orN
N
ONH2
O
S
N
CI
CI
N
N
OH
S
N
CI
CI
• Su
lfox
idation
• N-oxidation of p
yridinyl
nit
roge
n a
tom
• Hyd
roxylation
at iso
propy
l gr
oup
• B
u e
t al.,
200
4 (H
-Viv
o-P
O)
(HP
LC-R
AM
-MS)
• B
u e
t al.,
200
5, 2
006
(H-L
-M)
(HP
LC-R
AM
-MS)
• B
u e
t al.,
200
7 (R
-Viv
o-IV
; D
-Viv
o-P
O; R
+D
-L-M
)
(HP
LC-R
AM
-MS)
• O
hka
wa
et a
l., 1
998
(H+
Rm
-L-
M)
(HP
LC-M
S)
NR
NR
No
A.1
.9
Mit
omyc
in C
An
titu
mor
an
tib
ioti
c
N
O O
H2N
OCONH2
NH
OCH3
NNH2
SG
O O
H2N
• Enzymatic red
uction of
qu
inon
e• Open
ing of aziridine ring
• K
enn
edy
et a
l., 1
982
(Rm
-L-
M)
(UV
)• La
ng
et a
l., 2
005
(H-L
-M)
(HP
LC-M
S-D
AD
)• Pa
n e
t al.,
198
4 (R
-CY
P-N
AD
PH
) (H
PLC
-MS;
EP
R)
• Sc
hw
artz
, 196
2 (R
m-L
-M)
(U
V);
• To
mas
z an
d L
ipm
an, 1
981
(Rm
-L-M
) (U
V; N
MR
)
NR
NR
Yes
Tab
le 1
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 1.
Con
tin
ued
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No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.1
.10
Por
firo
myc
in
An
titu
mor
an
tib
ioti
c
N
O O
H2N
OCONH2
NCH3
OCH3
N
OPO3H
2
OOH2N
NHCH3
N
SCysNH2
OOH2N
NHCH3
• Enzymatic red
uction of
qu
inon
e• Open
ing of aziridine ring
• La
ng
et a
l., 2
000a
(R
-L-S
9;
H+
D-V
ivo-
IV)
(HP
LC-M
S-D
AD
; LSC
; NM
R)
• La
ng
et a
l., 2
000b
(R
-L-S
9)
(HP
LC-D
AD
-MS;
NM
R)
NR
NR
Yes
A.1
.11
Felb
amat
e
An
tiep
ilep
tic
OOONH2
ONH2
O
OH
O
NH2
ONH
HO
O
O ON
H2
OH
O
• 4-hyd
roxylation
of p
hen
yl
rin
g• Hyd
roxylation
of C
H group
• A
du
sum
alli
et a
l., 1
991
(Rm
-L-M
) (H
PLC
-RA
M)
• A
du
sum
alli
et a
l., 1
993
(H+
D-
Viv
o-P
O)
(HP
LC-R
AM
-MS)
• D
ieck
hau
s et
al.,
200
1 (H
+R
-V
ivo-
PO
) (H
PLC
-MS)
• K
apet
anov
ic e
t al.,
199
8 (H
-L-
S9+
M)
(HP
LC-U
V; G
C-M
S)• R
olle
r et
al.
2002
(H
SA)
(HP
LC-M
S)• R
oman
ysh
yn e
t al.,
199
4
(H-P
) (H
PLC
-UV
)• Th
omp
son
et a
l., 1
996,
199
7,
1999
, 200
0 (B
uff
er; H
-Viv
o-
PO
) (H
PLC
-MS-
DA
D)
• Ya
ng
et a
l., 1
991,
199
2 (R
+D
+R
abb
it-V
ivo-
PO
)
(HP
LC-U
V-R
AM
)
NR
NR
Yes
A.1
.12
Flu
orof
elb
amat
e
An
tiep
ilep
tic
O
OH
2N
OF
O NH
2
OH
O
FON
H2
Non
e re
por
ted
• Pa
rker
et a
l., 2
005
(H-L
-S9)
(H
PLC
-DA
D-M
S)• R
oeck
lein
et a
l., 2
007
(H-L
- S9
) (H
PLC
-DA
D-M
S)
NR
NR
Yes
Tab
le 1
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 1.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
556 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.1
.13
Mep
rob
amat
e
Mu
scle
rel
axan
t
H2N
OO
NH
2
OO
CO
2• Side-ch
ain oxidation
• B
ram
nes
s et
al.,
200
3 (H
-B)
(GC
; HP
LC-U
V)
• E
mm
erso
n e
t al.,
196
0 (R
m-V
ivo-
IP)
(TLC
; LSC
)• Lu
dw
ig e
t al.,
196
1 (H
+D
m-
Viv
o-P
O)
(LSC
; Pap
er C
)• P
hill
ips
et a
l., 1
962
(Rm
-Viv
o-IP
) (L
SC; P
aper
C)
• W
alke
nst
ein
et a
l., 1
958
(Rm
+D
m-V
ivo-
PO
+IP
; H
-Viv
o-P
O)
(LSC
; Pap
er C
)
NR
NR
No
A.1
.14
Meb
uta
mat
e
Hyp
oten
sive
ag
ent
H2N
OO
NH
2
OO
Non
e re
por
ted
• Side-ch
ain oxidation
• D
ougl
as e
t al.,
196
2 (D
m-V
ivo-
PO
) (P
aper
C;
NM
R)
• E
del
son
an
d D
ougl
as, 1
968
(R+
Rab
bit
-L-M
) (P
aper
C;
LSC
)
NR
0 No
Tabl
e 1.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 557
Tabl
e 2.
The
met
abol
ic h
ydro
lysi
s of
O-a
lkyl
carb
amat
es (
R3 =
Alk
yl; R
1 = A
lkyl
; R2 =
H o
r A
lkyl
).
NO
OR
3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.2
.1
Am
pre
nav
ir
HIV
-1 p
rote
ase
inh
ibit
or
NH
2
SN
OO
HNO
O
O
OH
NH
2
SN
OO
H2N
OH
• Oxidation of tetra-
hyd
rofu
ran
rin
g• Ring op
ening
• Oxidation of the
p-a
nili
ne
sulf
onat
e gr
oup
• Hyd
roxylation
of
anili
ne
rin
g• Hyd
roxylation
of
ben
zylic
pos
itio
n• Glucu
ronidation
• D
ecke
r, 19
98 (
H+
R+
D-
Viv
o-P
O)
(HP
LC-M
S)• Sa
dle
r et
al.,
200
1 (H
-Viv
o-P
O)
(LSC
; H
PLC
-F)
• Si
ngh
et a
l., 1
996
(H+
R+
Mon
key-
L-S9
) (H
PLC
-DA
D-M
S)• T
rélu
yer
et a
l., 2
003
(H
-L-M
) (H
PLC
-MS)
NR
e
+f
Yesg
A.2
.2
Rit
onav
ir
HIV
-1 p
rote
ase
inh
ibit
or
NN
OH
H
N
OO
HN H
O
O
SN
NS
CH
3
NN H
OH N
OO
HN
H2
SN
CH
3
• Hyd
roxylation
of
isop
ropy
l gro
up
• N-d
ealkylation of
ure
a gr
oup
• N-oxidation of u
rea
grou
p• Oxidation of
met
hyl
thia
zoly
l m
oiet
y• Glucu
ronidation
• D
enis
sen
et a
l., 1
997
(R
+D
-Viv
o-IV
+P
O+
ID;
H-V
ivo-
PO
) (H
PLC
-R
AM
-MS;
LSC
)• K
oud
riak
ova
et a
l., 1
998
(H-I
nte
stin
al-M
) (H
PLC
-R
AM
-MS)
• K
um
ar e
t al.,
199
6 (H
-L-M
) (H
PLC
-RA
M-M
S)• G
angl
et a
l., 2
002
(H-L
-M)
(HP
LC-M
S; N
MR
)
NR
+ Yes
A.2
.3
Car
met
hiz
ole
An
titu
mor
age
nt
SCH
3N N C
H3
H3C
HN
OC
O
OC
ON
HC
H3
SCH3
N N CH3
H3CHNOCO
OH
Non
e re
por
ted
• A
nd
erso
n e
t al.,
198
9 (B
uff
er)
(HP
LC-U
V; N
MR
)+ N
R
NR
Tab
le 2
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
558 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.2
.4
Doc
etax
el
An
titu
mor
ag
ent
OO
H
OH
O
O
OH
H N
O
O
O
HO
OO
O
O
OOH
OH
O
O
OH
N
O
HOO
OO
OO
HO
O
OOH
OH
O
O
OH
N
O
HOO
OO
OO
HO
O
OO
H
OH
O
O
OH
H N
O
O
O
HO
OO
HO
O
• Ring clos
ure
wit
h e
ith
er S
or
R
ster
eoch
emis
try
• Oxidation to
ox
azol
idin
dio
ne
• Oxidation at the
bac
cati
n m
oiet
y
• B
ard
elm
eije
r et
al.,
200
5 (M
ouse
-Viv
o-IV
) (H
PLC
-U
V-M
S; L
SC)
• G
uit
ton
et a
l., 2
005
(H-V
ivo-
IV)
(HP
LC-M
S)• R
osin
g et
al.,
200
0 (H
-Viv
o-IV
) (H
PLC
-MS)
• Sp
arre
boo
m e
t al.,
199
6 (H
-Viv
o) (
HP
LC-D
AD
-MS)
NR
NR
No
A.2
.5
Taxa
nes
An
titu
mor
ag
ents
O
OO
O
R'
Ac
O
O
OH
NH
O
O
OO
OH
OH
R
Non
e re
por
ted
• Hyd
roxylation
at R
si
de
chai
n• Los
s of propionyl on
C10
• Hyd
roxylation
of
met
hyl
on
the
C10
d
imet
hyl
amin
o
grou
p• Hyd
roxylation
of
arom
atic
rin
g
• G
ut e
t al.,
200
6 (H
+R
m+
Pig
+M
inip
ig-
L-M
) (H
PLC
-UV-
MS)
NR
0 (n
= 3
)
NR
A.2
.6
Ch
lora
lure
tan
e
Hyp
not
ic
CC
l 3
OH
N H
O
OC
Cl 3
OH
• O-glucu
ronation;
• N-d
ealkylation to
tr
ich
loro
eth
anol
• Oxidation to
tri-
chlo
roac
etic
aci
d
• G
lazk
o et
al.,
195
7 (H
+R
+D
m-V
ivo-
PO
)
(Pap
er C
; UV
)
NR
NR
Yes
A.2
.7
Car
baz
eran
An
tiar
ryth
mic
NN
N
OO
HN
H3CO
OCH3
OCH3
H3CO
NN
N
OH
• 4-hyd
roxylation
;• N-d
ealkylation to
N
-des
eth
yl-4
- h
ydro
xy c
arb
azer
an• Hyd
roxylation
on
pyp
erid
ine
rin
g• O-d
emethylation
• C
ritc
hle
y et
al.,
199
4 (G
uin
ea P
ig-V
ivo-
PO
) (H
PLC
-UV-
MS;
IR; L
SC)
• K
aye
et a
l., 1
984
(H+
Dm
-V
ivo-
PO
+IV
) (H
PLC
-UV
; T
LC-F
; LSC
)• K
aye
et a
l., 1
985
(H+
D+
Bab
oon
-L-C
) (H
PLC
-UV
)
NR
0 Yes
Tabl
e 2.
Con
tin
ued
.
Tab
le 2
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 559
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.2
.8
(2-o
xo-1
,3-
dio
xol-
4-yl
)m
eth
yl
carb
amat
es
(see
Tab
le 1
0)h
OCH3
OCH3
HN O
O
O
O
R
O
H2N
OCH3 OCH3
Non
e re
por
ted
• A
lexa
nd
er e
t al.,
199
6 (B
uff
er; R
+D
-P)
(H
PLC
-UV
)
+ (
n =
3)
++
(n
= 3
)
NR
A.2
.9
Am
inoc
arb
onyl
-ox
ymet
hyl
es
ters
(see
Ta
ble
11)
RN H
O
OO
O
R'
NH2
RN
one
rep
orte
d• M
end
es e
t al.,
200
2
(Bu
ffer
; H-P
) (H
PLC
-UV
)0/
+/+
+ (
n =
9)
++
(n
= 9
)
NR
A.2
.10
Am
inoc
arb
onyl
-ox
ymet
hyl
es
ters
(see
Ta
ble
11)
CH3
R'
RN
O
OO
O
CH3
R
H NN
one
rep
orte
d• M
end
es e
t al.,
200
2
(Bu
ffer
; H-P
) (H
PLC
-UV
)+
(n
= 2
)
++
(n
= 2
)
NR
A.2
.11
PE
G p
rod
rugs
of
dau
nor
ub
icin
(s
ee T
able
12)
An
titu
mor
ag
ents
CH3
H3C
H3C
R'R
O
O
O
O
O
OO
HO
HO
HO
OH
NH
OCH3
NH2 CH3
H3C
O
OO
OH
OH
O
OO
HO
HO
Non
e re
por
ted
• G
reen
wal
d e
t al.,
199
9 (B
uff
er; R
-P)
(HP
LC-U
V)
0 (n
= 4
)
+ (
n =
4)
NR
A.2
.12
Pro
dru
gs o
f R
WJ-
4451
67
(see
Tab
le 1
3)
Ora
l an
ti-
coag
ula
nt d
rug
RO
ONH O
O
N
H3C
HN
HN
HN
HN
OSO O
CH3
Non
e R
epor
ted
Non
e R
epor
ted
• M
arya
noff
et a
l., 2
006
(Rm
-Viv
o-P
O)
(HP
LC-M
S)N
R
NR
No
(n =
2)
Tabl
e 2.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
560 F. Vacondio et al.
Tabl
e 3.
The
met
abol
ic h
ydro
lysi
s of
O-a
lkyl
carb
amat
es (
R3 =
Alk
yl; R
1 = A
ryl o
r H
eter
oary
l or
Acy
l; R
2 = H
).
NO
OR3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.1
Eth
aciz
in
An
tiar
rhyt
hm
ic
NS
ON
N H
O
ON H
N H
SO
OH
• N-d
eethylation
• Su
lfox
idation
• N10
amido grou
p
hyd
roly
sis
• Hyd
roxylation
of the
arom
atic
rin
g
• B
elob
orod
ov e
t al.,
198
9 (H
-Viv
o-
PO
) (H
PLC
-UV
; UV
; IR
; NM
R; M
S)N
Re
NR
f
Yesg
A.3
.2
Mor
iciz
ine
An
tiar
rhyt
hm
ic
N HNS
O
O
O
NO
N HN H
OH
SO
NS
O
NH2
N
O
• Oxidation to
sulfox
ide
• Oxidative op
ening of
mor
ph
olin
e ri
ng
• Oxidative clea
vage
of
3-m
orp
hol
ino
pro
pio
-n
yl s
ide
chai
n
• P
ien
iasz
ek e
t al.,
199
4, 1
999
(H-V
ivo-
PO
) (H
PLC
-UV
; LSC
)• R
ich
ard
s et
al.,
199
7 (H
-Viv
o-P
O)
(HP
LC-U
V; N
MR
; MS)
• Ya
ng
and
Ch
an, 1
995
(Rm
-Viv
o-IV
; H
-Viv
o-P
O)
(HP
LC-U
V; M
S; IR
; T
LC)
NR
NR
Yes
A.3
.3
Zafi
rlu
kast
An
tias
thm
atic
N H
O
ON
HN
O
CH3
H3CO
SO
O
ON
HN
N H
OH3CO
SO
O
CH3
HN
H3CO
H2N
N
O SO
O
CH3
• N-d
emethylation at
ind
ole
nit
roge
n• Cleav
age of sulfon
a-m
ide
linka
ge• Cyclopen
tyl o
xidation
• To
lyl o
xidation
• Indole N-m
ethyl
oxid
atio
n
• K
assa
hu
n e
t al.,
200
5 (H
+R
-L-M
; R
m-V
ivo-
PO
) (H
PLC
-MS;
NM
R)
• Sa
vid
ge e
t al.,
199
8 (R
+D
+M
ouse
-V
ivo-
PO
; R+
D-V
ivo-
IV)
(HP
LC-
MS;
NM
R)
NR
+ Yes
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 561
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.4
Ret
igab
ine
An
tiep
ilep
tic
F
N H
H N
O
O
NH2
N HH NO
N H
O
FHN
NH
O
NH2
• N-d
ealkylation of the
flu
orob
enzy
lic s
ide
chai
n a
nd
su
bse
qu
ent
acet
ylat
ion
• Ring clos
ure rea
ctions
• N2- and
N4-
glu
curo
nid
atio
n
• H
emp
el e
t al.,
199
9 (H
+R
-L-S
lices
; H
-L-M
; H+
R+
D-V
ivo-
PO
) (H
PLC
- U
V-R
AM
-MS;
NM
R)
• H
iller
et a
l., 1
999
(H+
R+
D-L
-M;
H+
R+
D-V
ivo-
PO
) (H
PLC
-UV
; LSC
)• M
cNei
lly e
t al.,
199
7 (H
-L-M
+Sl
ices
) (H
PLC
-DA
D-R
AM
-MS)
NR
+ Yes
A.3
.5
Flu
pir
tin
e
An
alge
sic
F
N HN
H N
O
O
NH2
FHN
NNHO
NH2
• N-D
ealkylation of the
flu
oro-
ben
zylic
sid
e ch
ain
• Ring clos
ure rea
ctions
• H
lavi
ca a
nd
Nie
bch
, 198
5 (H
-Viv
o-P
O+
IV+
Rec
tal)
(H
PLC
-UV
; MS;
LS
C)
• O
ber
mei
er e
t al.,
198
5 (R
+D
-Viv
o-P
O+
IV)
(HP
LC-U
V; L
SC)
NR
NR
Yes
A.3
.6
Tira
cizi
ne
An
tiar
rhyt
hm
ic
N
O
(H3C) 2N
HN
O O(H3C) 2NN
ONH2
• Oxidative
N-d
emet
hyl
atio
n• K
lem
m e
t al.,
198
5 (R
-Viv
o-IV
+P
O)
(TLC
; LSC
)N
R
NR
Yes
A.3
.7
Pen
taca
ine
Loc
al
anes
thet
ic
O
H NO
O
N
OH
N• Aromatic ring
hyd
roxy
lati
on• Hyd
roxylation
of the
alip
hat
ic s
ide-
chai
n
• St
efek
an
d B
ezek
, 198
5 (R
m-L
-M
+H
epat
ocyt
es; R
m-p
erfu
sed
-L)
(GC
-MS)
• St
efek
et a
l., 1
986
(Rm
-L-M
+C
) (G
C-M
S; L
SC)
NR
+ NR
Tabl
e 3.
Con
tin
ued
.
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
562 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.8
Cam
ben
daz
ole
An
thel
min
tic
H N N
S
NN H
O
O
H N
N HO
N
S
NO
• Open
ing of th
e th
iazo
le r
ing
follo
wed
by
oxi
dat
ion
s an
d
dec
arb
oxyl
atio
n• Hyd
roxylation
of
isop
ropy
l gro
up
• Aromatic
hyd
roxy
lati
on
• V
and
enH
euve
l et a
l., 1
978
(Cat
tle+
Pig
+Sh
eep
-Viv
o-P
O)
(G
C-M
S; T
LC)
• W
olf e
t al.,
198
0 (H
amst
er-L
-M)
(GC
-FID
-MS;
NM
R; T
LC)
NR
NR
Yes
A.3
.9
Cap
ecit
abin
e
Thym
idyl
ate
sy
nth
etas
e in
hib
itor
O
N
OH
OH
N
O
FHN
O
OO
N
OH
HO
NO
F
H2N
• Oxidative clea
vage
of
4-a
min
o gr
oup
on
py
rim
idin
e ri
ng
• Red
uction to
dihyd
ro-
pyri
mid
ine
rin
g• Oxidative op
ening of
dih
ydro
pyri
mid
ine
ri
ng
• D
esm
oulin
et a
l., 2
002,
200
3 (R
m-V
ivo-
PO
) (H
PLC
-UV-
MS;
N
MR
)• Is
hik
awa
et a
l., 1
998
(H+
R-V
ivo-
PO
) (H
PLC
-MS)
• M
iwa
et a
l., 1
998
(H-L
-CE
S)
(HP
LC-U
V)
• R
eign
er e
t al.,
200
1 (H
-Viv
o-P
O)
(HP
LC-M
S-U
V; N
MR
)• Ts
uka
mot
o et
al.,
200
1 (H
-L-S
9/C
+G
ut-
S9/C
) (H
PLC
-MS)
NR
+ Yes
A.3
.10
Pro
dru
gs o
f O6 -
ben
zylg
uan
ine
DN
A r
epai
r in
acti
vato
rs
N H
O
COONa
ONO2
O
O
N
NNN R
O
HO
HO
OH
NH2
NN
NN
R
O
Non
e re
por
ted
• W
ei e
t al.,
200
5 (B
uff
er; R
-L-
Glu
curo
nid
ase)
(H
PLC
-UV
)0
(n =
2)
+(n
= 2
)
NR
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 563
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.11
Alb
end
azol
e
An
thel
min
tic
N HNS
OCH3
ONH
N H
NH2
NS
• Oxidation of sulfur to
sulf
oxid
e an
d s
ulf
one
• Side-ch
ain hyd
roxy
-la
tion
at t
he
β- a
nd
γ-
pos
itio
ns
• 6-hyd
roxylation
on
ben
zim
idaz
ole
rin
g• Methylation of b
oth
ben
zim
idaz
ole
nit
ro-
gen
s an
d s
ulf
ur
• Fa
rget
ton
et a
l., 1
986
(R-L
-M)
(HP
LC-U
V)
• G
okb
ulu
t et a
l., 2
007
(D-V
ivo-
PO
) (H
PLC
-DA
D)
• G
yuri
k et
al.,
198
1 (C
attl
e+Sh
eep
+
Rf+
Mou
se-V
ivo-
PO
) (L
SC; I
R;
NM
R; G
C-M
S; T
LC)
• M
arri
ner
an
d B
ogan
, 198
0 (S
hee
p-
Viv
o-P
O)
(HP
LC-U
V)
• M
erin
o et
al.,
200
3 (R
-L+
Inte
stin
e-
M; R
-Viv
o-P
O)
(HP
LC-U
V)
• M
oron
i et a
l., 1
995
(Rm
-L-M
)
(HP
LC-U
V-F
)• P
enic
aut e
t al.,
198
3 (H
-Viv
o-P
O)
(TLC
; LSC
; HP
LC-U
V)
• R
awd
en e
t al.,
200
0 (H
-L-M
) (H
PLC
-UV
)• R
olin
et a
l., 1
989
(H-L
-M+
hep
atom
a ce
lls)
(HP
LC-U
V; L
SC)
• So
uh
aili-
El A
mri
, et a
l., 1
987,
198
8 (R
m+
Pig
-L-M
+p
erfu
sed
live
rs)
(HP
LC-U
V; U
V; F
)• Ta
kaya
nag
ui e
t al.,
200
2 (H
-Viv
o-
PO
) (H
PLC
-F)
• V
elik
et a
l., 2
005
(Dee
r+C
attl
e+P
ig+
Shee
p-L
-M)
(HP
LC-F
)• V
illav
erd
e et
al.,
199
5 (R
f-in
test
ine-
M
) (H
PLC
-UV
)• V
irke
l et a
l., 2
000;
200
4 (S
hee
p+
Cat
tle-
L+lu
ng+
inte
stin
e-M
) (H
PLC
-UV
)
NR
+ Yes
A.3
.12
Cic
lob
end
azol
e
An
thel
min
tic
N HOCH3
N
OO
NH
N H
NH2
N
O
• 6-hyd
roxylation
of
ben
zim
idaz
ole
rin
g• Red
uction of k
eto
gr
oup
• B
rod
ie e
t al.,
197
7 (R
+D
-Viv
o-P
O)
(LSC
)• M
ayo
et a
l., 1
978
(R+
D-V
ivo-
PO
+IV
) (T
LC; L
SC; H
PLC
-UV-
MS;
NM
R)
NR
NR
Yes
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
564 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.13
Parb
end
azol
e
An
thel
min
tic
N
ON H
OCH3
N HN
one
rep
orte
d• Hyd
roxylation
of
5-b
uty
l ch
ain
at α
-,
β-, a
nd
δ-p
osit
ion
s• Oxidation of c
arbon
in
δ to
giv
e ca
rbox
ylic
ac
id• 6-hyd
roxylation
on
ben
zim
idaz
ole
rin
g• Oxidation of c
arbon
γ
to c
arb
onyl
gro
up
• D
icu
ollo
et a
l., 1
974
(Sh
eep
-Viv
o-
PO
) (L
SC; T
LC; U
V; M
S; IR
; NM
R)
• D
un
n e
t al.,
197
3 (S
hee
p+
Cat
tle-
Viv
o-P
O)
(UV
; MS;
NM
R)
NR
NR
No
A.3
.14
Meb
end
azol
e
An
thel
min
tic
NO
O
NHNHOCH3
N H
NH2
NO
• Red
uction of k
eto
gr
oup
• A
llan
an
d W
atso
n, 1
982,
198
3 (R
m-V
ivo-
IV)
(HP
LC-U
V; L
SC)
• B
ehm
et a
l., 1
983
(Sh
eep
-Viv
o-In
trar
um
inal
) (H
PLC
-UV
)• B
rugm
ans
et a
l., 1
971
(H-V
ivo-
PO
) (L
SC)
• D
awso
n e
t al.,
198
2, 1
985
(H-V
ivo-
PO
+IV
) (L
SC)
• G
ottm
ann
s et
al.,
199
1 (R
m-
per
fuse
d in
test
ine)
(H
PLC
-UV
)• Io
sifi
dou
et a
l., 1
997
(Eel
-Viv
o-P
O)
(HP
LC-U
V)
• M
euld
erm
ans
et a
l., 1
976
(Rm
+D
+P
ig-L
-M)
(TLC
; LSC
; MS)
NR
+ Yes
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 565
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.15
Fen
ben
daz
ole
An
thel
min
tic
NNH
NH
OCH3
S
O
NH
NNH2
S
• 4′
-hyd
roxy
lati
on
Sulf
oxid
atio
n• B
ench
aou
i an
d M
cKel
lar,
1996
(S
hee
p+
Goa
t-V
ivo-
PO
; Rf-
L-M
) (H
PLC
-UV
)• G
okb
ulu
t et a
l., 2
007
(D-V
ivo-
PO
) (H
PLC
-DA
D)
• M
cKel
lar
et a
l., 2
002
(Hor
se-V
ivo-
P
O+
Intr
acec
al; H
orse
-L-M
) (H
PLC
-UV
)• M
onte
siss
a et
al.,
198
9 (R
m+
Cat
tle+
Hor
se+
Shee
p+
Pig
+C
hic
ken
+T
rou
t-L-
M)
(HP
LC-U
V)
• M
urr
ay e
t al.,
199
2 (R
m-L
-M)
(HP
LC-U
V)
• P
eter
sen
et a
l., 2
000
(Pig
-Viv
o-
PO
+IV
) (H
PLC
-UV
)• Sa
nch
ez e
t al.,
200
3 (S
hee
p-V
ivo-
P
O)
(HP
LC-U
V)
• Sh
ort e
t al.,
198
8a, 1
988b
(Sh
eep
+
Ch
icke
n+
Du
ck+
Turk
ey+
Rab
bit
+
R+
Cat
fish
-L-S
9) (
HP
LC-U
V; M
S)• V
irke
l et a
l., 2
004
(Sh
eep
+C
attl
e-
L+ lu
ng+
inte
stin
e-M
) (H
PLC
-UV
)
NR
0 Yes
A.3
.16
N-(
Alk
oxy-
ca
rbon
yl)
carb
oxam
ide
der
ivat
ives
(s
ee T
able
14)
h
O
N H
O
OR
O NH2
Non
e re
por
ted
• K
ahn
s an
d B
un
dga
ard
, 199
1 (B
uff
er;
R-P
) (H
PLC
-UV
)+
(n
= 5
)
+ (
n =
3)
NR
A.3
.17
Feb
ante
l
An
thel
min
tic
NH NH
HN
OCH3 OCH3
H3CO
S
O
N
O
O
Non
e re
por
ted
• Cycliz
ation to
fe
nb
end
azol
e• Su
lfox
idation
• B
eret
ta e
t al.,
198
7 (R
m+
Hor
se+
C
attl
e+Sh
eep
+P
ig+
Ch
icke
n+
Tro
ut-
L-
M+
C)
(HP
LC-U
V)
• D
elat
our
et a
l., 1
983,
198
5 (S
hee
p-
Viv
o-P
O)
(HP
LC-U
V)
• M
onte
siss
a et
al.,
198
9 (R
m+
Cat
tle+
Hor
se+
Shee
p+
Pig
+C
hic
ken
+T
rou
t-L-
M)
(HP
LC-U
V)
NR
0 No
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
566 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.18
Mol
sid
omin
e
An
ti-a
ngi
nal
NO
NNO
NO O
N
O
NNO
HN
Non
e re
por
ted
• D
ell a
nd
Ch
amb
erla
in, 1
978
(H+
D-
Viv
o-P
O)
(HP
LC-U
V; L
SC)
• Fr
omso
n e
t al.,
198
1 (R
+D
+R
abb
it+
M
ouse
+M
onke
y-V
ivo-
PO
+IV
)
(LSC
)• Ta
nay
ama
et a
l., 1
970,
197
4 (R
m+
Mou
se-V
ivo-
PO
+IV
; Rm
-L-
Slic
es)
(TLC
; Pap
er C
; IR
; LSC
)• W
ilson
et a
l., 1
986,
198
7 (H
+R
+D
-V
ivo-
PO
; Rab
bit
-Viv
o-IV
) (H
PLC
- U
V; L
SC; G
C-M
S; N
MR
)
NR
+ Yes
A.3
.19
Dab
igat
ran
-et
exila
te
An
tith
rom
bot
ic
agen
tN
N
O
OO
NNCH3 HN
HNNH
OON
H
NH
2
HN
CH
3
NN
O
OH
O
NN
• Hyd
rolysis of th
e ethyl
este
r• Oxidation of the hex
yl
sid
e ch
ain
• B
lech
et a
l., 2
008
(H-V
ivo-
PO
+IV
; H
-L-M
; H-P
) (H
PLC
-F-U
V-R
AM
; H
PLC
-MS;
LSC
)• St
angi
er e
t al.
2005
(H
-Viv
o-P
O)
(HP
LC-M
S)
NR
+ Yes
A.3
.20
Lef
rad
afib
an
Pla
tele
t gly
co-
pro
tein
IIb
/II
Ia r
ecep
tor
anta
gon
ist
HN
HNO
O
OH N
OO
O
HN
H2N
OH N
OO
OH
Non
e re
por
ted
• M
ulle
r et
al.,
199
7 (H
-Viv
o-P
O)
(HP
LC-F
; LSC
)N
R
NR
Yes
A.3
.21
Car
bam
ate
pro
dru
gs o
f La
mifi
ban
(s
ee T
able
15)
Pla
tele
t gly
co-
pro
tein
IIb
-II
Ia r
ecep
tor
anta
gon
ist
N
OCOOR'''
OHN
ON
NH2
R'
R''O
Non
e re
por
ted
Non
e re
por
ted
• W
elle
r et
al.,
199
6 (M
ouse
-Viv
o-
PO
)N
R
NR
Yes
A.3
.22
Am
idin
o ca
rbam
ates
as
pro
dru
gs
(see
Tab
le 1
6)
Fact
or V
IIa
inh
ibit
ors
NH
N
H2N
OH
O OR
OH
Non
e re
por
ted
Non
e re
por
ted
• R
iggs
et a
l., 2
006
(H+
R-P
; H+
R-L
-M;
Rm
-Viv
o-P
O)
(HP
LC-M
S)N
R
0 (n
= 4
)
No
Tab
le 3
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 567
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
reA
ll id
enti
fied
met
abol
ites
der
ivin
g fr
om c
leav
age
of c
arb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.3
.23
Car
bam
ate
pro
dru
gs o
f 2,
5-b
is(4
- am
idin
o-
ph
enyl
)fu
ran
Ch
emio
ther
apic
ag
ent
O
N
NH
O
OR''
N
HN
O OR''
R'
R'
Non
e re
por
ted
Non
e re
por
ted
• R
ahm
ath
ulla
h e
t al.,
199
9 (R
-Viv
o-IV
+P
O)
NR
NR
Yes
A.3
.24
Car
bam
ate
pro
dru
g of
BII
L 28
4
LTB
4 rec
epto
r an
tago
nis
t
HO
OO
NH2
NO
O
HO
OO
NH2
NH
Non
e re
por
ted
• B
irke
et a
l., 2
001
(R+
Gu
inea
P
ig+
Mon
key-
Viv
o-P
O+
IV)
NR
NR
Yes
A.3
.25
Car
bam
ate
p
rod
rugs
of
fuse
d r
ing
d
icat
ion
ic
com
pou
nd
s R
= H
, Me,
Et
& i-
Pr
An
tip
roto
zoal
ag
ent
N H
HN
NN
NHR
O
OEt
OOEt
NHR
Non
e re
por
ted
Non
e re
por
ted
• A
rafa
et a
l., 2
005
(Mou
se-V
ivo-
P
O+
IP)
NR
NR
Yes
A.3
.26
Car
bam
ate
pro
dru
gs o
f 2-
guan
idin
oim
i-d
azol
ined
ion
e d
eriv
ativ
es
An
tim
alar
ial
agen
tCl Cl
NN
OO N NH
H N OO
Cl
Cl
HN
NNH
O ON
N
OO
Non
e re
por
ted
Non
e re
por
ted
• G
uan
et a
l., 2
005
(Mon
key-
V
ivo-
IM)
NR
NR
Yes
(n =
2)
Tabl
e 3.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
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tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
568 F. Vacondio et al.
Tabl
e 4.
The
met
abol
ic h
ydro
lysi
s of
O-a
lkyl
carb
amat
es h
avin
g an
en
doc
yclic
N-a
tom
.
NO
OR3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.4
.1
(Acy
loxy
)alk
yl
carb
amat
es o
f n
orfl
oxac
in
(see
Tab
le 1
7)h
An
tib
acte
rial
ag
ents
NN
O
O
RO
O
N
OH
OF
O
HN
N
NOH
O
FO
Non
e re
por
ted
• A
lexa
nd
er e
t al.,
199
1 (B
uff
er; H
+R
+D
- P
) (H
PLC
-UV
)0
(n =
1)e
++
(n
= 2
)f
NR
g
A.4
.2
Lor
atad
ine
H1-
rece
pto
r an
tago
nis
t
NCl
N
OO
NCl
N H
• 3-, 5
-, and
6-h
ydro
xyla
tion
• B
arec
ki e
t al.,
200
1 (H
-L-M
) (H
PLC
-D
AD
-F)
• H
ilber
t et a
l., 1
987
(H-V
ivo-
PO
) (R
IA;
HP
LC-F
)• K
atch
en e
t al.,
198
5 (H
-Viv
o-P
O)
(RIA
; H
PLC
-F)
• P
iwin
ski e
t al.,
199
0 (B
uff
er)
(HP
LC-
MS;
TLC
; NM
R)
• Yu
mib
e et
al.,
199
5, 1
996
(H-L
-M)
(H
PLC
-UV-
MS)
• R
aman
ath
an e
t al.,
200
5, 2
007
(H+
R+
Mou
se+
Mon
key-
Viv
o-P
O)
(HP
LC-M
S; L
SC)
+ + Yes
A.4
.3
Pro
dru
g of
d
oxaz
olid
ine
(R =
pen
tyl)
An
titu
mor
age
nt
OCH3
O O
OH
OH
O
OHO
ONO
HO
OO
R
OCH3
O O
OH
OH
O
OHO
ONH
O
HO
Non
e re
por
ted
• B
urk
har
t et a
l., 2
006
(Bu
ffer
; H
-P+
CE
S1+
CE
S2)
(HP
LC-U
V-F
)0 0 N
R
Tab
le 4
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 569
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.4
.4
N-(
alko
xy
carb
onyl
)
ph
enyt
oin
d
eriv
ativ
es
(see
Tab
le 1
8)
An
tiep
ilep
tics
NNH
O
O
O OR
HN
NH
O
O
Non
e re
por
ted
• Ta
nin
o et
al.,
199
8 (B
uff
er;
R-P
+L+
inte
stin
e) (
HP
LC-U
V)
0 (n
= 2
)
++
(n
= 2
)
NR
A.4
.5
1-al
koxy
-
carb
onyl
d
eriv
ativ
es o
f 5-
flu
orou
raci
l (s
ee T
able
19)
An
titu
mor
ag
ents
HN
N
FO
O
OOR
N H
NH
F OO
Non
e re
por
ted
• B
uu
r an
d B
un
dga
ard
, 198
6 (B
uff
er;
H-P
; Rab
bit
-Viv
o-re
ctal
) (U
V;
HP
LC-U
V)
+ (
n =
6)
++
(n
= 5
)
NR
A.4
.6
N-a
lkox
y-ca
rbon
yl
der
ivat
ives
of
thyr
otro
pin
- re
leas
ing
hor
mon
e (s
ee T
able
20)
N H
NH
N
O
N
N
O
RO
O
O
OH2N
N H
H NN
OHN
N
OO
O
H 2N
Non
e re
por
ted
• B
un
dga
ard
an
d M
øss,
199
0 (B
uff
er;
H-P
) (H
PLC
-UV
)• M
øss
et a
l., 1
990
(R+
Rab
bit
-gu
t)
(HP
LC-U
V)
0/+
(n
= 1
1)
+/+
+ (
n =
10)
NR
A.4
.7
N-a
lkox
y-ca
rbon
yl
der
ivat
ives
of
cim
etid
ine
(s
ee T
able
21)
An
tiu
lcer
dru
g
NN
S
NH
HN
NNC
O
OR
H3C
HN
N
S
NH
HN
NNC
H3C
Non
e re
por
ted
• B
uu
r an
d B
un
dga
ard
, 199
1 (B
uff
er;
H-P
; R-L
) (H
PLC
-UV
)0/
+ (
n =
5)
+ (
n =
5)
NR
Tab
le 4
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 4.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
570 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
A.4
.8
Mon
o- a
nd
dic
ar-
bam
ates
of (
R)-
α-
met
hyl
-his
tam
ine
(see
Tab
le 2
2)
His
tam
ine
H3
rece
pto
r ag
onis
tsN N
H N
O
O
OOR
HR'
N N H
H N
O
OR'
H
Non
e re
por
ted
• St
ark
et a
l., 2
001
(Bu
ffer
; R-L
; Mou
se-
Viv
o-P
O)
(RIA
)0
(n =
2)
0 (n
= 4
)
NR
A.4
.9
1H-i
mid
azol
e-1-
ca
rbox
ylat
es o
f R
OS2
03
(see
Tab
le 2
3)
His
tam
ine
H3
rece
pto
r
anta
gon
ists
NN
SSN
O
OR
HN
N
SSN
Non
e re
por
ted
• R
ivar
a et
al.,
200
8 (B
uff
er; H
+R
-P;
R-L
+B
rain
) (H
PLC
-UV
)+
/++
(n
= 8
)
+/+
+ (
n =
8)
NR
Tabl
e 4.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
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tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 571
Tabl
e 5.
The
met
abol
ic h
ydro
lysi
s of
O-a
rylc
arb
amat
es (
R3 =
Ary
l; R
1 = A
lkyl
, R2 =
H).
NO
OR3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.1
.1
N-(
sub
stit
ute
d
2-h
ydro
xyp
ropy
l)ca
rbam
ate
pro
dru
g of
par
acet
amol
(s
ee T
able
24)
h
H NO
OOH
N H
OO
R
OONHO
R
OH
H N
O
Non
e re
por
ted
• V
igro
ux
et a
l., 1
995
(Bu
ffer
; H+
R-P
) (H
PLC
-UV
; NM
R)
+ (
n =
2)e
++
(n
= 2
)f
NR
g
B.1
.2
Ary
lcar
bam
ates
(s
ee T
able
25)
ArONH
RO
ArOH
Non
e re
por
ted
• H
uan
g et
al.,
199
3 (H
+M
ouse
+R
-L-M
) (U
V)
++
(n
= 1
)
0 (n
= 3
)
NR
B.1
.3
Car
bam
ate
d
eriv
ativ
es o
f ty
rosy
l pep
tid
es
(see
Tab
le 2
6)
NH
O
H2N
O
O
O
H NR
NH
O
H2N
O
OH
Non
e re
por
ted
• K
ahn
s an
d B
un
dga
ard
, 199
1 (B
uff
er;
H-P
; R-L
) (H
PLC
-UV
)+
(n
= 2
)
+ (
n =
2)
NR
B.1
.4
Ary
l car
bam
ates
(s
ee T
able
27)
Inh
ibit
ors
of F
AA
H
(fat
ty a
cid
am
ide
hyd
rola
se)
OO NH
RR
R'
R''
HO
R
R'
R''
Non
e re
por
ted
• V
acon
dio
et a
l., 2
009
(Bu
ffer
; R-P
; R-
L-S9
) (H
PLC
-UV-
MS)
+/+
+ (
n =
10)
+/+
+ (
n =
10)
NR
Tab
le 5
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
572 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.1
.5
N-a
lkyl
- ca
rbam
ates
(se
e Ta
ble
28)
Dop
amin
ergi
c p
rod
rugs
N
OCl
OO NH
R
CH3
N
OCl
HO
CH3
Non
e re
por
ted
• H
anse
n e
t al.,
199
1 (B
uff
er; H
+R
+
D-P
) (H
PLC
-UV
)+
+ (
n =
6)
++
(n
= 6
)
NR
B.1
.6
Ph
enyl
car
bam
ates
of
su
bst
itu
ted
et
hyl
1,2
-dia
min
es
(see
Tab
le 2
9)
ON
NO
R
R'
R''
OH
Non
e re
por
ted
• Th
omse
n e
t al.,
199
4 (B
uff
er; H
-P;
R+
Pig
-L)
(HP
LC-U
V)
+ (
n =
3)
+ (
n =
3)
NR
B.1
.7
N-a
lkyl
-car
bam
ic
este
rs o
f en
taca
pon
e (s
ee
Tab
le 3
0)
CO
MT
Inh
ibit
ors
NO2OH
O
ON HR
N
O
N
NO2 OH
OH
CN
O N
Non
e re
por
ted
• Sa
vola
inen
et a
l., 2
000
(Bu
ffer
; H-P
) (H
PLC
-UV
)+
(n
= 3
)
+ (
n =
3)
NR
Tabl
e 5.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 573
Tabl
e 6.
The
met
abol
ic h
ydro
lysi
s of
O-a
rylc
arb
amat
es (
R3 =
Ary
l; R
1 = R
2 = A
lkyl
, or
N-e
nd
ocyc
lic). N
OO
R3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.2
.1
Riv
asti
gmin
e
Ace
tylc
hol
ine-
ster
ase
(Ach
E)
inh
ibit
orO
N(CH3)2
N
OH3C
OH
N(CH3)2
• N-d
emethylation
• H
abu
cky
and
Tse
, 199
8 (R
abb
it-V
ivo-
PO
+IV
) (L
SC; G
C-M
S)• P
olin
sky,
199
8 (H
+R
+D
-Viv
o-P
O+
IV)
(LSC
; GC
-MS)
• Ts
e an
d L
apla
nch
e, 1
998
(Min
ipig
- V
ivo-
PO
+IV
+d
erm
al)
(LSC
)
NR
e
+f
Yesg
B.2
.2
Bam
bu
tero
l
Pro
dru
g of
β2-
rece
pto
r ag
onis
tO
O
O
(H3C) 2N
O
(H3C) 2N
OH
N H
OH
HO
OH
N H
• Hyd
roxylation
of
met
hyl
gro
up
s on
ca
rbam
ate
nit
roge
n• N-d
emethylation
• Li
nd
ber
g et
al.,
198
9 (R
m-L
-M)
(HP
LC-M
S; L
SC)
• N
yber
g et
al.,
199
8 (H
-Viv
o-IV
+P
O)
(GC
-MS)
• R
yrfe
ldt e
t al.,
198
8 (G
uin
ea P
ig-l
un
g)
(LSC
)• Sv
enss
on a
nd
Tu
nek
, 198
8 (H
+R
+
Gu
inea
pig
-L-M
; H-V
ivo-
PO
) (H
PLC
-MS)
• Tu
nek
et a
l., 198
8 (H
+R+Guinea
p
ig+
Mou
se+
D+
rab
bit
-B)
(HP
LC-M
S)• Tu
nek
and Sve
nsson
, 198
8 (H
-B) (U
V)
NR
+ Yes
B.2
.3
Est
ram
ust
ine
An
titu
mor
age
nt
OH
O
O
NCl
Cl
OH
HO
• Dep
hos
phor
ylation
• 17
-oxidation to
es
tron
e
• A
nd
erss
on e
t al.,
198
1(H
-Viv
o-P
O)
(GC
-MS;
RIA
)• B
erge
nh
eim
an
d H
enri
ksso
n, 1
998
(H-V
ivo-
IV+
PO
) (L
SC)
• C
arb
one
and
Dix
on, 1
979
(D-V
ivo-
PO
) (L
SC)
• D
ixon
et a
l., 1
980
(H+
D+
Rm
-Viv
o-P
O)
(HP
LC-F
)• K
ird
ani e
t al.,
197
5, 1
977
(H+
Bab
oon
+D
+R
-Viv
o-P
O+
IV)
(LSC
)• G
un
nar
sson
et a
l., 1
984
(H-V
ivo-
PO
) (L
SC)
NR
NR
Yes
Tab
le 6
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
574 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.2
.4
Ph
enyl
ca
rbam
ates
of
sub
stit
ute
d e
thyl
d
iam
ines
(se
e Ta
ble
29)
h
ON
N
OR
R'
R''
OH
Non
e re
por
ted
• Th
omse
n e
t al.,
199
4 (B
uff
er; H
-P;
R+
Pig
-L)
(HP
LC-U
V)
+/+
+ (
n =
4)
+/+
+ (
n =
4)
NR
B.2
.5
N,N
-dia
lkyl
-ca
rbam
ates
(s
ee T
able
28)
Dop
amin
ergi
c p
rod
rugs
NCH3
O
Cl O
O
NR
R'
NCH3
O
Cl
HO
Non
e re
por
ted
• H
anse
n e
t al.,
199
1 (B
uff
er; H
+R
+D
-P)
(HP
LC-U
V)
0 (n
= 3
)
0 (n
= 3
)
NR
B.2
.6
Cam
azep
am
An
xiol
ytic
N
NO
Cl
OO(H3C) 2N
CH3
N
NO
Cl
CH3
HO
• Hyd
roxylation
of o
ne
or
two
N-m
eth
yl
grou
ps
of th
e ca
r-b
amat
e, fo
llow
ed b
y N
-dem
eth
ylat
ion
• Oxidative N-
dea
lkyl
atio
n o
n N
1
• Ic
him
aru
, 198
4 (H
-Viv
o-P
O)
(LSC
)• Lu
an
d Y
ang,
199
3 (R
-L-M
) (H
PLC
-U
V-M
S)• M
orin
o et
al.,
198
5 (M
ouse
+R
m+
D+
Mon
key-
Viv
o-IV
+P
O)
(LSC
; TLC
)• N
akam
ura
et a
l., 1
986
(Rm
-Viv
o-
PO
+IV
) (L
SC; T
LC; H
PLC
-UV
; NM
R)
NR
+ Yes
B.2
.7
Neo
stig
min
e
Ach
E in
hib
itor
O
O
N(CH3)2
(H3C) 3N
OH
(H3C) 3N
Non
e re
por
ted
• B
urd
fiel
d e
t al.,
197
3 (R
m-L
-M+
C)
(L
SC; p
aper
ele
ctro
ph
ores
is)
• H
usa
in e
t al.,
196
9 (R
-Viv
o-IM
) (L
SC;
pap
er e
lect
rop
hor
esis
)• R
ober
ts e
t al.,
196
6, 1
968
(Rm
-Viv
o-
PO
; Rm
-L-M
) (L
SC; p
aper
el
ectr
oph
ores
is)
• Sc
ott e
t al.,
196
2 (H
-Viv
o-P
O+
IM)
(p
aper
C)
NR
+ Yes
Tab
le 6
. co
nti
nu
ed o
n n
ext p
age
Tabl
e 6.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 575
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.2
.8
Pyr
idos
tigm
ine
Ach
E in
hib
itor
NO
O
N(CH3)2
H3C
NOH
H3C
Non
e re
por
ted
• B
urd
fiel
d e
t al.,
197
3 (R
m-L
-M+
C)
(L
SC; p
aper
ele
ctro
ph
ores
is)
• H
usa
in e
t al.,
196
8 (R
m-V
ivo-
PO
)
(LSC
; pap
er e
lect
rop
hor
esis
)
NR
+ Yes
B.2
.9
Mu
ragl
itaz
ar
Act
ivat
or o
f th
e p
erox
isom
e p
ro-
lifer
ator
-act
ivat
ed
rece
pto
r (P
PAR
)O
NO
OH
OOOCH
3
N O
Non
e re
por
ted
• Hyd
roxylation
• O-d
emethylation
• O-d
ealkylation
• Carbox
ylic acid
form
atio
n• Oxa
zole ring op
ening
• Li
et a
l., 2
006
(Mou
se-V
ivo-
PO
) (L
SC;
HP
LC-U
V-M
S)• W
ang
et a
l., 2
006
(H-V
ivo-
PO
) (L
SC;
HP
LC-D
AD
-RA
M-M
S)• Z
han
g et
al.,
200
6 (H
-Viv
o-P
O)
(LSC
; H
PLC
-DA
D-M
S; N
MR
)• Z
han
g et
al.,
200
7a, 2
007b
(H
+R
+D
+M
onke
y-V
ivo-
PO
; H+
R-
Mon
key-
hep
atoc
yte;
H-L
-M)
(LSC
; H
PLC
-DA
D-R
AM
-MS)
NR
0 No
B.2
.10
Irin
otec
an
An
titu
mor
dru
g
NN
O OHO
OO
N
N
ON
N
O OHO
OHO
• Hyd
roxylation
of termi-
nal
pip
erid
ine
rin
g• Oxidative clea
vage
of
one
or b
oth
α-c
arb
ons
of
ou
ter
pip
erid
ine
ri
ng
• Ring op
ening
• Oxidation of c
amp
-to
thec
in n
ucl
eus
• Oxidation of terminal
pip
erid
ine
rin
g w
ith
lo
ss o
f 2H
• D
odd
s et
al.,
199
8 (H
-Viv
o-IV
; H-L
-M)
(HP
LC-F
-MS)
• H
aaz
et a
l., 1
997
(H-L
-M)
(HP
LC-F
)• K
aned
a et
al.,
199
0 (M
ouse
-L+
Inte
stin
e-S9
; Mou
se-P
; Mou
se-
Viv
o-IV
) (H
PLC
-F)
• L
okie
c et
al.,
199
6 (H
-Viv
o-IV
)
(HP
LC-F
-MS)
• M
ath
ijsse
n e
t al.,
200
1 (H
-Viv
o-IV
; H
-L-M
; H-C
ES)
(H
PLC
-F-M
S)• R
ivor
y et
al.,
199
5, 1
996
(H-V
ivo-
IV)
(HP
LC-F
-MS;
NM
R)
• Sa
i, 20
01 (
H-L
-M)
(HP
LC-M
S)• Sa
ngh
ani e
t al.,
200
4 (H
-L-C
ES)
(H
PLC
-F)
• Sa
nto
s et
al.,
200
0 (H
-Viv
o-IV
; H-L
-M)
(HP
LC-M
S)• Sl
atte
r et
al.,
199
7, 2
000
(H-L
-M;
H-V
ivo-
IV)
(HP
LC-F
-RA
M-M
S; L
SC)
• X
ie e
t al.,
200
3 (M
ouse
-L-C
ES)
(H
PLC
-F)
NR
+ Yes
Tabl
e 6.
Con
tin
ued
.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
576 F. Vacondio et al.
Tabl
e 7.
The
met
abol
ic h
ydro
lysi
s of
O-a
rylc
arb
amat
es (
R3 =
Ary
l; R
1 = A
ryl;
R2 =
H o
r A
lkyl
or
Oth
er).
NO
OR3
R1
R2
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
B.3
.1
Gan
stig
min
e
AC
hE
inh
ibit
or
N HO
NN
OCH3 OH
H3C
CH3
HO
NNCH3 OH
H3C
CH3
• Aromatic oxidation
• N-red
uction
• N-d
emethylation at
bot
h n
itro
gen
s• Oxidation of e
thyl
chai
n
• C
atin
ella
et a
l., 2
001
(R+
D+
Mon
key-
L-M
) (H
PLC
-UV-
MS)
• P
eliz
zi e
t al.,
200
3 (H
+R
+D
+M
onke
y-h
epat
ocyt
es)
(HP
LC-M
S)
NR
e
+f
NR
g
B.3
.2
Car
zele
sin
An
titu
mor
age
nt
ONCl
HN
OO
NH
HN
O
O
N(C
2H5)2
H NH
ONCl
HN HO
HN
O
O
N(C
2H5)2
NN
one
rep
orte
d• A
wad
a et
al.,
199
9 (H
-Viv
o-IV
) (H
PLC
-UV
)• Li
et a
l., 1
992
(Bu
ffer
; H+
Mou
se-P
) (H
PLC
-UV
)• V
an T
ellin
gen
et a
l., 1
998a
, 199
8b
(H+
R+
Mou
se-V
ivo-
IV)
(HP
LC-U
V)
0 ++
Yes
B.3
.3
Car
bam
ate
d
eriv
ativ
es o
f m
eth
yltr
iaze
nes
(s
ee T
able
31)
h
An
titu
mor
age
nts
N NN H
N
OCH2Ph
NN
NH3C
ORO
Non
e re
por
ted
Non
e re
por
ted
• W
ann
er e
t al.,
200
4 (B
uff
er)
(NM
R)
+/+
+ (
n =
6)
NR
NR
B.3
.4
N-(
sub
stit
ute
d-
hyd
roxy
ph
enyl
) ca
rbam
ates
(se
e Ta
ble
32)
Skel
etal
mu
scle
re
laxa
nts
; an
alge
sics
; an
tipy
reti
cs
O OHN O
H3C
NH
OH R
ROH N
O
Non
e re
por
ted
• V
igro
ux
et a
l., 1
995
(Bu
ffer
; R+
H-P
) (H
PLC
-UV
; NM
R)
++
(n
= 3
)
++
(n
= 3
)
NR
B.3
.5
O-p
hen
yl
carb
amat
es o
f N
-su
bst
itu
ted
2-
amin
o-
ben
zam
ides
(s
ee T
able
33)
O
HN
RN
O OR''
R'
N
N
OR'
RO
Non
e re
por
ted
• Th
omse
n a
nd
Bu
nd
gaar
d, 1
993
(B
uff
er; H
-P)
(HP
LC-U
V)
0/+
(n
= 1
6)
+/+
+ (
n =
14)
NR
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 577
Tabl
e 8.
The
met
abol
ic h
ydro
lysi
s of
cyc
lic c
arb
amat
es.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
C.1
.1
Efa
vire
nz
HIV
-1 r
ever
se-
tran
scri
pta
se
inh
ibit
or
Cl
N H
O
F 3C
O
Cl
NH2OH
F 3C
• Hyd
roxylation
on C7 an
d C8
• Hyd
roxylation
on cyclo-
pro
pan
e ri
ng
• N-G
lucu
ronidation
• B
um
pu
s et
al.,
200
6 (H
-L-
CY
P)
(HP
LC-U
V; U
V-V
IS)
• M
auri
n e
t al.,
200
2 (B
uff
er)
(HP
LC-U
V-M
S)• M
utl
ib e
t al.,
199
9a
(H+
R+
Mon
key-
L+ki
dn
ey-
S9+
M+
C; H
+R
+G
uin
ea
pig
+H
amst
er+
Mon
key-
Vi-
vo-P
O)
(HP
LC-M
S-N
MR
)• M
utl
ib e
t al.,
199
9b
(Rm
-Viv
o-P
O)
(HP
LC-M
S-N
MR
)• M
utl
ib e
t al.,
200
0 (R
-Viv
o-
PO
) (H
PLC
-MS)
• W
ard
et a
l., 2
003
(H-L
-M+
C
YP
) (H
PLC
-UV-
MS)
+e
0f Nog
C.1
.2
Met
axal
one
Mu
scle
rel
axan
t
CH3
CH3
OO
HN
O
14C
O2
• Oxidation of m
ethyl to
ca
rbox
ylic
aci
d• Cleav
age of th
e ether linka
ge
• B
ruce
et a
l., 1
966
( H
+D
-V
ivo-
PO
) (U
V; I
R; T
LC)
NR
NR
No
C.1
.3
Lin
ezol
id
An
tib
acte
rial
d
rug
NO
F
NO
O
NHAc
Non
e re
por
ted
• Hyd
roxylation
of the
m
orp
hol
ine
rin
g to
the
h
emia
ceta
l met
abol
ite
• Morpholine ring op
ening to
carb
oxyl
ic a
cid
an
d d
iol
• Sl
atte
r et
al.,
200
1 (H
-Viv
o-
PO
) (L
SC; H
PLC
- R
AM
-UV-
MS;
NM
R)
• W
ynal
da
et a
l., 2
000
(H
-L-M
) (H
PLC
-RA
M-M
S)
NR
0 No
C.1
.4
Alk
enyl
-d
iary
lmet
han
es
(AD
AM
)(se
e Ta
ble
34)
h
Non
-nu
cleo
sid
e
HIV
inh
ibit
ors
F
RR'
H3CO
H3CO
N
OO
Non
e re
por
ted
Non
e re
por
ted
• D
eng
et a
l., 2
005
(R-P
) (H
PLC
-UV
)N
R
0 (n
= 2
)
NR
Tab
le 8
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
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from
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578 F. Vacondio et al.
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
C.1
.5
Telit
hro
myc
in
An
tib
acte
rial
ag
ent
OO
(H3C) 2N
OH O
OON
O
O
OCH3
O
NN
N
Non
e re
por
ted
• Los
s of aryl rings
• N-d
emethylation on
des
osam
ine
rin
g• N-oxidation of p
yridine
• N
amou
r et
al.,
200
1 (H
-Viv
o-P
O)
(HP
LC-M
S)• P
erre
t et a
l., 2
002
(H-V
ivo-
PO
+IV
) (H
PLC
-MS)
• Sh
i et a
l. 20
05 (
H-V
ivo-
PO
) (L
SC).
NR
NR
No
C.1
.6
CD
RI-
85/9
2
An
tiu
lcer
age
nt
NH
OO
HOOC
Non
e re
por
ted
• Cis-trans isom
erization
• Oxidation of side ch
ain
• Sr
ivas
tava
et a
l., 2
004
(Rm
-L-
S9+
M+
C; R
m-V
ivo-
PO
) (H
PLC
-MS;
UV
)
NR
0 No
C.1
.7
E 2
011
MA
O-A
inh
ibit
orO
NO
S
NH3CO
OH
CN
Non
e re
por
ted
• O-d
emethylation
• 4-hyd
roxylation
on
oxaz
olid
inon
e ri
ng
• Hyd
roxylation
of side ch
ain
• N
aito
h e
t al.,
199
7a
(Rm
-Viv
o-P
O)
(LSC
; TLC
; H
PLC
-F-R
AM
; MS;
NM
R)
• N
aito
h e
t al.,
199
7b (
Rm
+
D-V
ivo-
PO
) (H
PLC
-F; T
LC;
LSC
)
NR
NR
No
C.1
.8
Cim
oxat
one
MA
O-A
inh
ibit
or
NO
O
OH3CO
CN
Non
e re
por
ted
• O-d
emethylation
• Oxidation to
carbox
ylic acid
• Cleav
age of te
rminal phen
yl
rin
g• Hyd
roxylation
of the
ox
azol
idin
one
rin
g
• R
ovei
et a
l., 1
984
(H-V
ivo-
P
O)
(HP
LC-U
V)
NR
NR
No
C.1
.9
TAK
-536
An
giot
ensi
n II
re
cep
tor
an
tago
nis
t
O
N HN
O
NN
COOH
EtO
H2NHN
NN
COOH
EtO
Non
e re
por
ted
• K
ohar
a et
al.,
199
5, 1
996
(Rm
-Viv
o-P
O)
NR
NR
Yes
Tabl
e 8.
Con
tin
ued
.
Tab
le 8
. co
nti
nu
ed o
n n
ext p
age
Dru
g M
etab
olis
m R
evie
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nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 579
No.
/nam
eP
har
mac
olog
ical
cl
ass
Ch
emic
al s
tru
ctu
re
All
iden
tifi
ed m
etab
olit
es
der
ivin
g fr
om c
leav
age
of
carb
amat
e gr
oup
Dir
ectl
y co
mp
etit
ive
reac
tion
sR
efer
ence
s an
d c
ond
itio
nsa–
d
Est
imat
ed
hyd
roly
sis
and
co
mm
ents
e–g
C.1
.10
1,2,
4-ox
adia
zol-
5-
one
der
ivat
ive
as p
rod
rug
of
amid
ine
grou
p
(see
Tab
le 3
5)
Pla
tele
t gly
co-
pro
tein
IIb
-III
a re
cep
tor
an
tago
nis
tN
NCOOH
OH
COOMe
ON H
OMe
NO
NH
O
O
NN
COOH
OH
COOMe
ON H
OMe
HN H 2N
O
Non
e re
por
ted
• K
itam
ura
et a
l., 2
001
(Gu
inea
P
ig-P
+L+
smal
l in
test
ine;
G
uin
ea P
ig-V
ivo-
PO
)
(HP
LC-U
V)
NR
+/0
(n
= 1
)
Yes
C.1
.11
3-ar
ylaz
o-1,
2,4-
oxad
iazo
l-5-
ones
as
pro
dru
gs o
f N
O-d
onor
s
An
tith
rom
bot
ic
agen
t
NNH
OO
NN R
Non
e re
por
ted
Non
e re
por
ted
• R
ehse
et a
l., 1
997
(R-
Viv
o-P
O)
NR
NR
Yes
C.1
.12
Bis
-1,2
,4-
oxad
iazo
l-5-
one
as p
rod
rug
of
bis
-alk
ylam
ido-
oxim
e
An
tim
alar
ial
agen
t
NN
10
NO
ON
OO
CH3
H3C
H NH N
10
NOH
OH
N
CH3
CH3
Non
e re
por
ted
• O
uat
tara
et a
l., 2
007
(M
ouse
-Viv
o-P
O+
IP)
NR
NR
Yes
a Spec
ies:
H, h
um
an; R
, rat
; Rm
, mal
e ra
t; R
f, fe
mal
e ra
t; D
, dog
.bIn
viv
o/in
vit
ro/o
rgan
/tis
sue:
Viv
o, in
viv
o; V
ivo-
PO
, per
os;
Viv
o-IV
, i.v
.; V
ivo-
IM, i
.m.;
Viv
o-ID
, in
trad
uod
enal
; L, l
iver
; P, p
lasm
a or
ser
um
; B, b
lood
.c In
vit
ro p
rep
arat
ion
: S9,
9,0
00-g
su
per
nat
ant;
M, m
icro
som
es; C
, cyt
osol
; CE
S, c
arb
oxyl
este
rase
; CY
P, c
ytoc
hro
me
P45
0.dA
nal
ytic
al te
chn
iqu
e: D
AD
, dio
de-
Arr
ay d
etec
tor;
IR, i
nfr
ared
sp
ectr
osco
py; U
V, u
ltra
viol
et s
pec
tros
copy
or d
etec
tor;
HP
LC, h
igh
-per
form
ance
liq
uid
ch
rom
atog
rap
hy;
GC
, gas
ch
rom
atog
rap
hy;
T
LC, t
hin
-lay
er c
hro
mat
ogra
ph
y; L
SC, l
iqu
id s
cin
tilla
tion
cou
nti
ng;
MS,
mas
s sp
ectr
omet
ry; F
ID, fl
ame
ion
izat
ion
det
ecto
r; R
AM
, rad
iom
etri
c d
etec
tor;
F, fl
uor
esce
nce
det
ecto
r; E
PR
, ele
ctro
n
par
amag
net
ic r
eson
ance
; NM
R, n
ucl
ear
mag
net
ic r
eson
ance
.e,
f Firs
t row
: ch
emic
al h
ydro
lysi
s; s
econ
d r
ow: i
n v
itro
met
abol
ism
. Rat
e or
ext
ent o
f hyd
roly
sis:
NR
= n
ot r
epor
ted
; 0 =
nu
ll to
low
; + =
low
to m
ediu
m; +
+ =
med
ium
to h
igh
.g Th
ird
row
: in
viv
o m
etab
olis
m. Y
es =
met
abol
ite
du
e to
car
bam
ate
clea
vage
ob
serv
ed; N
o =
met
abol
ite
du
e to
car
bam
ate
clea
vage
not
ob
serv
ed o
r ob
serv
ed t
o a
min
ute
ext
ent
(< 5
% o
f to
tal
met
abol
ism
cou
ld b
e at
trib
ute
d to
hyd
roly
tic
clea
vage
).hSe
e Su
pp
lem
enta
ry M
ater
ial.
Tabl
e 8.
Con
tin
ued
.
Dru
g M
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olis
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580 F. Vacondio et al.
et al., 2007), while none were observed in humans and rats, indicating significant species differences in terms of identities and relative abundance of circulating capra-virine metabolites.
Table 2 presents O-alkylcarbamates with monoalkyl or dialkyl substitution on the nitrogen. Table 2 includes a number of drugs, plus five series of potential carbamate prodrugs (A.2.8, A.2.9, A.2.10, A.2.11, and A.2.12), whose details are compiled in Supplementary Tables 10, 11, 12, and 13. In a few cases, cleavage of the carbamate group was demonstrated to be catalyzed by cytochrome P450 enzymes. Thus, the N-decarbamoylated metabolite of the HIV-1 protease inhibitor, amprenavir (A.2.1), necessitated the presence of NADPH in human liver S
9 incubations for
its formation, implicating the involvement of cytochrome P450 (Singh et al., 1996). The same was true for the HIV-1 protease inhibitor, ritonavir (A.2.2) (Kumar et al., 1996).
The hydrolysis of carmethizole (A.2.3) in aqueous neutral buffer at 25°C proceeded with a half-life of ca. 150 minutes, forming an initial monocarbamate, which, itself, had a hydrolytic half-life of 22 hours. Hydrolysis of the isomeric, synthetic monocarbamate was much faster (t
1/2 ∼ 30 minutes). This shows that the reactivity of the
two carbamate moieties in carmethizole are significantly different, with the higher reactivity of the C-5 carbamate moiety being rationalized by sulfur participation in the elimination of the carbamate moiety (Anderson et al., 1989). Carbamate prodrugs of the oxyguanidine-based dual inhibitor of thrombin and factor Xa RWJ-445167 (A.2.12 and Supplementary Table 13) are also reported.
Although methyl and ethyl carbamates were quickly absorbed after oral administration to rats, neither compound was converted in vivo into the parent drug (Maryanoff et al., 2006).
Table 3 contains O-alkylcarbamates monosubsti-tuted on the nitrogen atom by an aryl, heteroaryl, or acyl moiety. Many representatives with an N-heteroaryl sub-stituent are benzimidazole anthelmintics bearing a car-bamate group in the 2-position of the ring. Their product of carbamate hydrolysis was identified in all these cases, except parbendazole (A.3.13). In the case of mebendazole (A.3.14), whose metabolism was extensively investigated in a number of animal species, ketone reduction was the more important metabolic route in rats in vivo, account-ing for two thirds of a dose after conjugation; carbamate hydrolysis accounted only for about 1.7%. In contrast, the product of hydrolysis was the major unconjugated metab-olite detected in human urine. In the case of parbenda-zole, the indication “none reported” states that no proof of hydrolytic cleavage was found in available literature data. Series A.3.16 in Table 3 is presented in greater detail in the Supplementary Table 14. Another populated subcategory of Table 3 is that of carbamate prodrugs of aryl amidines and guanidines. Two significative examples are dabigatran etexilate (A.3.19), a double prodrug of the direct thrombin inhibitor, dabigatran, and lefradafiban (A.3.20), a double prodrug of the platelet glycoprotein IIb/IIIa receptor antagonist, fradafiban. After oral administration, both prodrugs were converted into the active drug via hydroly-sis of the alkyl ester and of the N-alkoxycarbonyl moiety
Table 9. A summary of the qualitative data in Tables 1–8, including the series covered in Tables 10–31 (Supplementary Material).
Hydrolysis in buffer In vitro hydrolysis In vivo hydrolysis Total data (n) Scorea– + ++ – + ++ No Yes
Table 1 Alkyl-O-CO-NH
2
0 0 0 6 0 0 6 8 20 0.4
Table 2 Alkyl-O-CO-NH-Alkyl or Alkyl-O-CO-N(Alkyl)
2
5 13 1 4 6 14 3 4 50 1.1
Table 3 Alkyl-O-CO-NH-Aryl or Alkyl-O-CO-NH-Heteroaryl or Alkyl-O-CO-NH-Acyl
2 5 0 6 13 0 3 21 50 0.8
Table 4 Alkyl-O-CO-N(endocyclic)
11 25 1 5 22 18 0 1 83 1.0
Table 5 Aryl-O-CO-NH-Alkyl
0 16 15 3 12 12 0 0 58 1.4
Table 6 Aryl-O-CO-N(Alkyl)
2 or Aryl-O-
CO-N(endocyclic)
3 1 3 4 7 3 1 7 29 0.9
Table 7 Aryl-O-CO-NH-Aryl or Aryl-O-CO-N(Alkyl)Aryl or Aryl-O-CO-N(other)Aryl
1 5 1 0 1 1 0 1 10 —
Table 8 Cyclic carbamates
0 1 0 7 1 0 7 4 20 0.3
aTotal of points (− = 0; + = 1; ++ = 2; No = 0; Yes = 1) divided by the numer of data (n) and rounded off to the first decimal place. A score was calculated only when n > 10 and the number of metabolic datapoints was larger than the number of data points in buffers.
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Hydrolysis of carbamates: qualitative structure-metabolism relationships 581
by unspecified esterases (Blech et al., 2008; Muller et al., 1997). The N-carbamoylation of basic and protonated amidine or guanidine groups, as a strategy to improve oral bioavailability and overall in vivo pharmacological activity, is also the focus of the prodrug design reported from A.3.21 to A.3.26. It must be noted, however, that direct identification of the metabolite deriving from in vivo cleavage of the carbamate group is seldom reported by the investigators, and this explains our comment “none reported” in column IV of Table 3. The observed in vivo pharmacological activity after peripheral administration of the prodrug is the indirect proof, presented by the investigators, that metabolic cleavage has taken place and that the active drug has been released from the prodrug moiety. However, data interpretation may be complicated, because, in some cases, it cannot be rigorously excluded that the carbamate itself shows some pharmacological activity (e.g., A.3.23) or that pharmacokinetic factors other than prodrug stability (e.g., poor oral absorption or distribution) could be evoked to explain the reported in vivo data.
Table 4 focuses on O-alkyl carbamates having an endocyclic N-atom, the majority of which are prodrug candidates that released the parent compound after in vitro incubations in biological media known to have high hydrolytic activity (i.e., plasma, liver, and intestine homogenates). A special behavior is that of (acyloxy)alkyl carbamates of norfloxacin (A.4.1 and Supplementary Table 17); esterase-catalyzed hydrolysis of these modi-fied carbamates triggered the regeneration of the parent amine through the intermediate formation of an unstable carbamic acid. The other series of candidate prodrugs are detailed in Supplementary Tables 18–23. The only full drug in Table 4 is loratadine (A.4.2); yet, its hydro-lyzed metabolite is also an effective antiallergic agent. Interestingly, the formation of this metabolite was also found to be CYP dependent.
Table 5 focuses on the O-arylcarbamates having one or two alkyl groups on the nitrogen atom. Table 5 begins with a series of two N-(2-hydroxypropyl)carbamates (B.1.1 and Supplementary Table 24), which were not consid-ered in our search for qualitative structure-metabolism relations (SMRs); indeed, their mechanism of carbamate cleavage is a specific base-catalyzed intramolecular nucleophilic attack, resulting in cyclization and libera-tion of metaxalone or mephenoxalone, respectively. But, the story does not end here, since compounds B.1.1 are, in fact, dual prodrugs, with the intramolecular reaction also liberating paracetamol. The other series in Table 5 (series B.1.2–B.1.7) are detailed in the Supplementary Tables 25–30.
Table 6 features O-arylcarbamates bearing a dialkyl-substituted or endocyclic nitrogen atom. Some com-pounds in this class are prodrugs whose activation can occur by hydrolysis or CYP-catalyzed oxidation of an
N-alkyl substituent. This is illustrated by the activation of bambuterol (B.2.2) to terbutaline; both the hydrolytic and oxidative routes act cooperatively for optimal bioac-tivation. Serum cholinesterases predominantly catalyzed hydrolysis, while hydroxylation of the methyl groups, followed by elimination of formaldehyde, was due to CYPs. Similarly, camazepam (B.2.6) was metabolized by stepwise demethylation with mono- and dihydroxymeth-ylated metabolites as intermediates; this pathway forms the decarbamoylated metabolite known as oxazepam. This dual mechanism does not appear to be a general rule for this class of carbamates, as CYPs were not involved in the decarbamoylation of rivastigmine (B.2.1).
Table 7 features N,O-diarylcarbamates, as exempli-fied by ganstigmine (B.3.1) and carzelesin (B.3.2), the latter being a prodrug. The carbamates of a methyltria-zene derivative (B.3.3 and Supplementary Table 31) are not strictly N,O-diaryl carbamates, but have been arbi-trarily classified here given the conjugated character of the N-substituent. The two subsequent series of poten-tial prodrugs, N-(2-hydroxyphenyl)carbamates (B.3.4) and N-(2-carboxamidophenyl)carbamates (B.3.5) (see Supplementary Tables 32 and 33, respectively), are, again, special, in that their activation proceeds by an intramo-lecular nucleophilic attack. Like the series B.1.1 in Tables 5 and 24, these two series were not taken into account in our search for qualitative SMRs. Indeed, and taking series B.3.5 as an example, its high reactivity observed in neutral solutions was shown to be purely nonenzymatic.
Table 8 outlines the specific class of cyclic carbamates, be they six-membered (efavirenz, C.1.1) or five- membered drugs (C.1.2–C.1.12). The majority of these drugs share the property of being metabolically stable, as far as the cyclic carbamate moiety is concerned. Degradation, fol-lowed by ring opening, was observed for efavirenz (C.1.1), but under drastic experimental conditions at 60°C over a pH range from 0.6 to 12.8 (Maurin et al., 2002). Mass spectra data identified a break-down product, with molecular weight consistent with the hydrolysis of the cyclic carbamate to the corresponding amino alcohol. The metabolic stability of the oxazolidinone ring was, for example, confirmed by the fact that only traces of 14CO
2
were obtained from rats receiving metaxalone (C.1.2) 14C-labeled on the carbonyl carbon. Metabolic cleavage was also reported for 1,2,4-oxadiazol-5-one derivatives, which are designed to be cyclic prodrugs of amidines. In the clinical trials of the potent angiotensin II receptor antagonist, TAK-536 (C.1.9), the 1,2,4-oxadiazol-5-one ring was converted in vivo to an amidino group in one of the metabolites (Kohara et al., 1995). Metabolic conver-sion of the 1,2,4-oxadiazol-5-one ring to amidine was also observed in vitro by Kitamura et al. (2001) in the presence of guinea pig liver homogenate, but not in the presence of plasma or small-intestine homogenate. This prompted the investigators to suggest that an oxidative cleavage
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582 F. Vacondio et al.
catalyzed by cytochrome P450 could take place, involving the cleavage of the N-O bond in the 1,2,4-oxadiazol-5-one ring, followed by the elimination of carbon dioxide from the carbamicacid intermediate.
Qualitative SMRs
Table 9 was set up to summarize all qualitative data reported in Tables 1–8, plus the quantitative data in Supplementary Tables 10–35. Carbamates reacting intramolecularly were excluded from this compilation (series B.1.1 in Table 5; B.3.4 and B.3.5 in Table 7). The qualitative data in Tables 1–8 mainly contributed to pop-ulate the in vivo hydrolysis column of Table 9, for which a yes/no answer was given for the in vivo cleavage of the carbamate group. The quantitative data in Tables 10–35 were more difficult to encode. A three-level score was chosen (–, +, and ++), based on half-lives of hydrolytic reactions in abiotic media (i.e., buffers) or in in vitro bio-logical preparations (e.g., blood plasma, homogenates). Specifically, the symbol “–“ was chosen to mean t
1/2 >
48 hours, while the symbol “++” was attributed to t1/2
< 1 hour. Half-lives in the intermediate range (1 hour < t
1/2 < 48
hours) were encoded by the symbol “+”.A final score, representing the metabolic lability of the
carbamate group to hydrolytic cleavage, was calculated for each row in Table 9. This score was calculated by attrib-uting a numerical value to each symbol, namely: – = 0; + = 1; ++ = 2; No = 0; Yes = 1 (see also footnotes in Table 9) and normalizing the resulting total for the number of data points (n). A score was calculated only when n > 10 and when the number of enzymatic data points (in vivo and in vitro) was larger than the number of abiotic half-lives (in buffers). This led us to exclude, from the final scor-ing, the class of carbamates in Table 7 (O-aryl carbamates with an aryl amino group), which, based on our criteria, was not sufficiently populated. All remaining chemical classes of carbamates did fulfill our criteria.
It can be seen from Table 9 that the trend convexed by the score was such that metabolic lability toward hydrolysis decreased (i.e., stability increased) in the fol-lowing series: Aryl-OCO-NHAlkyl >> Alkyl-OCO-NHAlkyl ∼ Alkyl-OCO-N(Alkyl)
2 ≥ Alkyl-OCO-N(endocyclic) ≥ Aryl-
OCO-N(Alkyl)2 ∼ Aryl-OCO-N(endocyclic) ≥ Alkyl-OCO-
NHAryl ∼ Alkyl-OCO-NHAcyl >> Alkyl-OCO-NH2 > Cyclic
carbamates. The last two classes appeared, clearly and markedly, more stable than the others. In contrast, the first class was particularly labile. The other classes fell in between, and their differences were modest enough to appear fortuitous. Yet, given the rather large number of data points in most classes, the trend unveiled here should be indicative enough to be taken into consideration when designing carbamate drugs and prodrugs endowed with a nominal range of stability toward metabolic hydrolysis.
Supplementary material
Tables 10–35 can be found at the website of the Medicinal Chemistry Group at the Dipartimento Farmaceutico, Università degli Studi di Parma (Available at: www.unipr.it/arpa/dipfarm/medchem/). Access date: from May 2010.
Acknowledgements
The authors are grateful to Emeritus Prof. Pier Vincenzo Plazzi for his kind interest during the early phases of the project
Declaration of interest
Research support from the University of Parma is grate-fully acknowledged. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
Adusumalli, V. E., Wong, K. K., Kucharczyk, N., Sofia, R. D. (1991). Felbamate in vitro metabolism by rat liver microsomes. Drug Metab Dispos 19:1135–1138.
Adusumalli, V. E., Choi, Y. M., Romanyshyn, L. A., Sparadoski, R. E., Wichmann, J. K., Wong, K. K., et al. (1993). Isolation and iden-tification of 3-carbamoyloxy-2-phenylpropionic acid as a major human urinary metabolite of felbamate. Drug Metab Dispos 21:710–716.
Alexander, J., Fromtling, R. A., Bland, J. A., Pelak, B. A., Gilfillan, E. C. (1991). (Acyloxy)alkyl carbamate prodrugs of norfloxacin. J Med Chem 34:78–81.
Alexander, J., Bindra, D. S., Glass, J. D., Holahan, M. A., Renyer, M. L., Rork, G. S., et al. (1996). Investigation of (oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chi-ral amines. J Med Chem 39:480–486.
Allan, R. J., Watson, T. R. (1982). Identification of biliary metabolites of mebendazole in the rat. Eur J Drug Metab Pharmacokinet 7:131–136.
Allan, R. J., Watson, T. R. (1983). The metabolic and pharmacoki-netic disposition of mebendazole in the rat. Eur J Drug Metab Pharmacokinet 8:373–381.
Anderson, W. K., Bhattacharjee, D., Houston, D. M. (1989). Design, synthesis, antineoplastic activity, and chemical properties of bis(carbamate) derivatives of 4,5-bis (hydroxyl methyl)imidazole. J Med Chem 32:119–127.
Andersson, S. B., Gunnarsson, P. O., Nilsson, T., Forshell, G. P. (1981). Metabolism of estramustine phosphate (Estracyt) in patients with prostatic carcinoma. Eur J Drug Metab Pharmacokinet 6:149–154.
Arafa, R. K., Brun, R., Wenzler, T., Tanious, F. A., Wilson, W. D., Stephens, C. E., et al. (2005). Synthesis, DNA affinity, and anti-protozoal activity of fused ring dicationic compounds and their prodrugs. J Med Chem 48:5480–5488.
Awada, A., Punt, C. J., Piccart, M. J., Van Tellingen, O., Van Manen, L., Kerger, J., et al. (1999). Phase I study of carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule. Br J Cancer 79:1454–1461.
Bardelmeijer, H. A., Roelofs, A. B., Hillebrand, M. J., Beijnen, J. H., Schellens, J. H., van Tellingen, O. (2005). Metabolism of docetaxel in mice. Cancer Chemother Pharmacol 56:299–306.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 583
Barecki, M. E., Casciano, C. N., Johnson, W. W., Clement, R. P. (2001). In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes. Drug Metab Dispos 29: 1173–1175.
Behm, C. A., Cornish, R. A., Bryant, C. (1983). Mebendazole concen-trations in sheep plasma. Res Vet Sci 34:37–41.
Beloborodov, V. L., Rodionov, A. P., Tyukavkina, N. A., Klimov, A. V., Kaverina, N. V., Kolesnik Yu, A., et al. (1989). Ethacizin metabo-lism in humans. Xenobiotica 19:755–767.
Benchaoui, H. A., McKellar, Q. A. (1996). Interaction between fenben-dazole and piperonyl butoxide: pharmacokinetic and pharmaco-dynamic implications. J Pharm Pharmacol 48:753–759.
Beretta, C., Fadini, L., Stracciari, J. M., Montesissa, C. (1987). In vitro febantel transformation by sheep and cattle ruminal fluids and metabolism by hepatic subcellular fractions from different ani-mal species. Biochem Pharmacol 36:3107–3114.
Bergenheim, A. T., Henriksson, R. (1998). Pharmacokinetics and phar-macodynamics of estramustine phosphate. Clin Pharmacokinet 34:163–172.
Billings, R. E., McMahon, R. E., Ashmore, J., Wagle, S. R. (1977). The metabolism of drugs in isolated rat hepatocytes. A comparison with in vivo drug metabolism and drug metabolism in subcellular liver fractions. Drug Metab Dispos 5:518–526.
Birke, F. W., Meade, C. J., Anderskewitz, R., Speck, G. A., Jennewein, H. M. (2001). In vitro and in vivo pharmacological characteriza-tion of BIIL 284, a novel and potent leukotriene B(4) receptor antagonist. J Pharmacol Exp Ther 297:458–466.
Blech, S., Ebner, T., Ludwig-Schwellinger, E., Stangier, J., Roth, W. (2008). The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 36:386–399.
Bramness, J. G., Skurtveit, S., Fauske, L., Grung, M., Molven, A., Morland, J., et al. (2003). Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics 13:383–388.
Brodie, R. R., Mayo, B. C., Chasseaud, L. F., Hawkins, D. R. (1977). The disposition of radioactivity after administration of the anthelmin-thic methyl-14C-5-cyclopropylcarbonyl-2-benzimidazole car-bamate (ciclobendazole) to rats and dogs. Arzneim-Forsch Drug Res 27:593–598.
Bruce, R. B., Turnbull, L., Newman, J., Pitts, J. (1966). Metabolism of metaxalone. J Med Chem 9:286–288.
Bruce, R. B., Turnbull, L., Newman, J. (1971). Metabolism of methocarbamol in the rat, dog, and human. J Pharm Sci 60: 104–106.
Brugmans, J. P., Thienpont, D. C., van Wijngaarden, I., Vanparijs, O. F., Schuermans, V. L., Lauwers, H. L. (1971). Mebendazole in entero-biasis. Radiochemical and pilot clinical study in 1,278 subjects. JAMA 217:313–316.
Brumfitt, W., Kosmidis, J., Hamilton-Miller, J. M., Gilchrist, J. N. (1974). Cefoxitin and cephalothin: antimicrobial activity, human phar-macokinetics, and toxicology. Antimicrob Agents Chemother 6:290–299.
Bu, H. Z., Pool, W. F., Wu, E. Y., Raber, S. R., Amantea, M. A., Shetty, B. V. (2004). Metabolism and excretion of capravirine, a new non-nucleoside reverse transcriptase inhibitor, alone and in combi-nation with ritonavir in healthy volunteers. Drug Metab Dispos 32:689–698.
Bu, H. Z., Kang, P., Zhao, P., Pool, W. F., Wu, E. Y. (2005). A simple sequential incubation method for deconvoluting the complicated sequential metabolism of capravirine in humans. Drug Metab Dispos 33:1438–1445.
Bu, H. Z., Zhao, P., Kang, P., Pool, W. F., Wu, E. Y. (2006). Identification of enzymes responsible for primary and sequential oxygenation reactions of capravirine in human liver microsomes. Drug Metab Dispos 34:1798–1802.
Bu, H. Z., Zhao, P., Kang, P., Pool, W. F., Wu, E. Y., Shetty, B. V. (2007). Evaluation of capravirine as a CYP3A probe substrate: in vitro and in vivo metabolism of capravirine in rats and dogs. Drug Metab Dispos 35:1593–1602.
Bumpus, N. N., Kent, U. M., Hollenberg, P. F. (2006). Metabolism of efavirenz and 8-hydroxyefavirenz by P450 2B6 leads to inac-tivation by two distinct mechanisms. J Pharmacol Exp Ther 318:345–351.
Buhler, D. R. (1964). The metabolism of chlorphenesin carbamate. J Pharmacol Exp Ther 145: 232–241.
Buhler, D. R. (1965). Characterization of the glucuronide conjugate of chlorphenesin carbamate from the rat and from man. Biochem Pharmacol 14:371–373.
Buhler, D. R., Harpootlian, H., Johnston, R. L. (1966). The absorption, excretion, and metabolism of chlorphenesin carbamate in the dog. Biochem Pharmacol 15:1507–1521.
Buhler, D. R., Harpootlian, H. (1967). Metabolism of 3-(p-chlorophenoxy)-2-methoxypropyl carbamate in the rat. Proc Soc Exp Biol Med 125:469–471.
Buhs, R. P., Maxim, T. E., Allen, N., Jacob, T. A., Wolf, F. J. (1974). Analysis of cefoxitin, cephalothin, and their deacylated metabo-lites in human urine by high-performance liquid chromatogra-phy. J Chromatogr 99:609–618.
Bundgaard, H., Moss, J. (1990). Prodrugs of peptides. 6. Bioreversible derivatives of thyrotropin-releasing hormone (TRH) with increased lipophilicity and resistance to cleavage by the TRH-specific serum enzyme. Pharm Res 7:885–892.
Burdfield, P. A., Calvey, T. N., Roberts, J. B. (1973). In vitro metabo-lism of neostigmine and pyridostigmine. J Pharm Pharmacol 25:428–429.
Burkhart, D. J., Barthel, B. L., Post, G. C., Kalet, B. T., Nafie, J. W., Shoemaker, R. K., et al. (2006). Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases. J Med Chem 49:7002–7012.
Buur, A., Bundgaard, H. (1986). Prodrugs of 5-fluorouracil V. 1-alkox-ycarbonyl derivatives as potential prodrug forms for improved rectal or oral delivery of 5-fluorouracil. J Pharm Sci 75:522–527.
Buur, A., Bundgaard, H. (1991). Prodrugs of cimetidine with increased lipophilicity: N-acyloxymethyl and N-alkoxycarbonyl derivatives. Acta Pharm Nord 1:51–56.
Campbell, A. D., Coles, F. K., Eubank, L. L., Huf, E. G. (1961). Distribution and metabolism of methocarbamol. J Pharmacol Exp Ther 131:18–25.
Carbone, J. J., Dixon, R. (1979). Estramustine phosphate: metabolism in the dog. Fed Proc 38:442.
Catinella, S., Pelizzi, N., Puccini, P., Marchetti, S., Zanol, M., Acerbi, D., et al. (2001). Phase I metabolism of ganstigmine. Rat, dog, monkey, and human liver microsomal extracts investigated by liquid chromatography electrospray tandem mass spectrometry. J Mass Spectrom 36:1287–1293.
Critchley, D. J., Rance, D. J., Beedham, C. (1994). Biotransformation of carbazeran in guinea pig: effect of hydralazine pretreatment. Xenobiotica 24:37–47.
Dawson, M., Allan, R. J., Watson, T. R. (1982). The pharmacokinetics and bioavailability of mebendazole in man: a pilot study using [3H]-mebendazole. Br J Clin Pharmacol 14:453–455.
Dawson, M., Watson, T. R. (1985). The effect of dose form on the bioavailability of mebendazole in man. Br J Clin Pharmacol 19:87–90.
Decker, C. J., Laitinen, L. M., Bridson, G. W., Raybuck, S. A., Tung, R. D., Chaturvedi, P. R. (1998). Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 87:803–807.
Delatour, P., Tiberghien, M. P., Besse, S. (1983). An HPLC procedure for the quantification of five metabolites of febantel in sheep serum. J Vet Pharmacol Ther 6:233–235.
Delatour, P., Tiberghien, M. P., Garnier, F., Benoit, E. (1985). Comparative pharmacokinetics of febantel and its metabolites in sheep and cattle. Am J Vet Res 46:1399–1402.
Dell, D., Chamberlain, J. (1978). Determination of molsidomine in plasma by high-performance liquid column chromatography. J Chromatogr 146:465–473.
Deng, B. L., Hartman, T. L., Buckheit, R. W., Pannecouque, C., De Clercq, E., Fanwick, P. E., et al. (2005). Synthesis, anti-HIV activ-ity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 48:6140–6155.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
584 F. Vacondio et al.
Denissen, J. F., Grabowski, B. A., Johnson, M. K., Buko, A. M., Kempf, D. J., Thomas, S. B., et al. (1997). Metabolism and disposition of the HIV-1 protease inhibitor ritonavir (ABT-538) in rats, dogs, and humans. Drug Metab Dispos 25:489–501.
Desmoulin, F., Gilard, V., Malet-Martino, M., Martino, R. (2002). Metabolism of capecitabine, an oral fluorouracil prodrug: 19F-NMR studies in animal models and human urine. Drug Metab Dispos 30:1221–1229.
Desmoulin, F., Gilard, V., Martino, R., Malet-Martino, M. (2003). Isolation of an unknown metabolite of capecitabine, an oral 5-fluorouracil prodrug, and its identification by nuclear mag-netic resonance and liquid chromatography-tandem mass spec-trometry as a glucuroconjugate of 5′-deoxy-5-fluorocytidine, namely 2′-(beta-D-glucuronic acid)-5′-deoxy-5-fluorocytidine. J Chromatogr B Analyt Technol Biomed Life Sci 792:323–332.
Dicuollo, C. J., Miller, J. A., Mendelson, W. L., Pagano, J. F. (1974). Metabolic and tissue residue studies on parbendazole in sheep. J Agric Food Chem 22:948–953.
Dieckhaus, C. M., Santos, W. L., Sofia, R. D., Macdonald, T. L. (2001). The chemistry, toxicology, and identification in rat and human urine of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one: a reac-tive metabolite in felbamate bioactivation. Chem Res Toxicol 14:958–964.
Dixon, R., Brooks, M., Gill, G. (1980). Estramustine phosphate: plasma concentrations of its metabolites following oral administration to man, rat, and dog. Res Commun Chem Pathol Pharmacol 27:17–29.
Dodds, H. M., Haaz, M. C., Riou, J. F., Robert, J., Rivory, L. P. (1998). Identification of a new metabolite of CPT-11 (irinotecan). Pharmacological properties and activation to SN-38. J Pharmacol Exp Ther 286:578–583.
Douglas, J. F., Ludwig, B. J., Ginsberg, T., Berger, F. M. (1962). The metabolic fate of mebutamate (Capla). J Pharmacol Exp Ther 136:5–9.
Dunn, G. L., Gallagher, G., Davis, L. D., Hoover, J. R., Stedman, R. J. (1973). Metabolites of methyl 5(6)-butyl-2-benzimidazolecar-bamate (Parbendazole). Structure and synthesis. J Med Chem 16:996–1002.
Edelson, J., Douglas, J. F. (1968). In vitro metabolism of mebutamate. Arch Int Pharmacodyn Ther 173:182–188.
Edelson, J., Douglas, J. F., Ludwig, B. J. (1969). Chlorphenesin metabo-lism in the rat and dog. Biochem Pharmacol 18:2331–2338.
Emmerson, J. L., Miya, T. S., Yim, G. K. (1960). The distribution and metabolic state of carbon-14 meprobamate in the rat brain. J Pharmacol Exp Ther 129:89–93.
Ettmayer, P., Amidon, G., Clement, B., Testa, B. (2004). Lessons learned from marketed and investigational prodrugs. J Med Chem 47:2393–2404.
Fargetton, X., Galtier, P., Delatour, P. (1986). Sulfoxidation of albenda-zole by a cytochrome P450–independent monooxygenase from rat liver microsomes. Vet Res Commun 10:317–324.
Fromson, J. M., Illing, H. P., Ings, R. M., Johnson, K. I., Johnson, P., Ostrowski, J., et al. (1981). Absorption and disposition of [14C]-molsidomine in laboratory animals. Arzneim-Forsch Drug Res 31:337–345.
Gangl, E., Utkin, I., Gerber, N., Vouros, P. (2002). Structural elucidation of metabolites of ritonavir and indinavir by liquid chromatogra-phy-mass spectrometry. J Chromatogr A 974:91–101.
Glazko, A. J., Dill, W. A., Wolf, L. M., Kazenko, A. (1957). Metabolic disposition of ethyl trichloramate. J Pharmacol Exp Ther 121:119–129.
Gokbulut, C., Bilgili, A., Hanedan, B., McKellar, Q. A. (2007). Comparative plasma disposition of fenbendazole, oxfendazole, and albendazole in dogs. Vet Parasitol 148:279–287.
Gottmanns, H., Kroker, R., Ungemach, F. R. (1991). Investigations on the biotransformation of mebendazole using an isolated perfused rat gut system. Xenobiotica 21:1431–1439.
Greenwald, R. B., Pendri, A., Conover, C. D., Zhao, H., Choe, Y. H., Martinez, A., et al. (1999). Drug delivery systems employing 1,4- or 1,6-elimination: poly(ethylene glycol) prodrugs of amine-containing compounds. J Med Chem 42:3657–3667.
Guan, J., Zhang, Q., Montip, G., Karle, J. M., Ditusa, C. A., Milhous, W. K., et al. (2005). Structure identification and prophylactic
antimalarial efficacy of 2-guanidinoimidazolidinedione deriva-tives. Bioorg Med Chem 13:699–704.
Guitton, J., Cohen, S., Tranchand, B., Vignal, B., Droz, J-P., Guillaumont, M., et al. (2005). Quantification of docetaxel and its main metabolites in human plasma by liquid chromatogra-phy/tandem mass spectrometry. Rapid Commun Mass Spectrom 19:2419–2426.
Gunnarsson, P. O., Andersson, S. B., Johansson, S. A., Nilsson, T., Plym Forshell, G. (1984). Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancer patients. Eur J Clin Pharmacol 26:113–119.
Gut, I, Ojima, I, Vaclavikova, R, Simek, P, Horsky, S, Linhart, I, et al. (2006). Metabolism of new-generation taxanes in human, pig, minipig, and rat liver microsomes. Xenobiotica 36:772–792.
Gyurik, R. J., Chow, A. W., Zaber, B., Brunner, E. L., Miller, J. A., Villani, A. J., et al. (1981). Metabolism of albendazole in cattle, sheep, rats, and mice. Drug Metab Dispos 9:503–508.
Haaz, M. C., Rivory, L. P., Riche, C., Robert, J. (1997). The transfor-mation of irinotecan (CPT-11) to its active metabolite, SN-38, by human liver microsomes. Differential hydrolysis for the lactone and carboxylate forms. Naunyn Schmiedebergs Arch Pharmacol 356:257–262.
Habucky, K., Tse, F. L. (1998). Disposition of SDZ ENA 713, an acetyl-cholinesterase inhibitor, in the rabbit. Biopharm Drug Dispos 19:285–290.
Hansen, K. T., Faarup, P., Bundgaard, H. (1991). Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion. J Pharm Sci 80:793–798.
Hempel, R., Schupke, H., McNeilly, P. J., Heinecke, K., Kronbach, C., Grunwald, C., et al. (1999). Metabolism of retigabine (D-23129), a novel anticonvulsant. Drug Metab Dispos 27:613–622.
Hilbert, J., Radwanski, E., Weglein, R., Luc, V., Parentesis, G., Symchowicz, S., et al. (1987). Pharmacokinetics and dose pro-portionality of loratadine. J Clin Pharmacol 27:694–698.
Hiller, A., Nguyen, N., Strassburg, C. P., Li, Q., Jainta, H., Pechstein, B., et al. (1999). Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos 27:605–612.
Hlavica, V. P., Niebch, G. (1985). Pharmacokinetics and biotransfor-mation of the analgesic flupirtine in humans. Arzneim-Forsch Drug Res 35:67–74.
Huang, T. L., Szekacs, A., Uematsu, T., Kuwano, E., Parkinson, A., Hammock, B. D. (1993). Hydrolysis of carbonates, thiocar-bonates, carbamates, and carboxylic esters of alpha-naphthol, beta-naphthol, and p-nitrophenol by human, rat, and mouse liver carboxylesterases. Pharm Res 10:639–648.
Husain, M. A., Roberts, J. B., Thomas, B. H., Wilson, A. (1968). Excretion and metabolism of oral pyridostigmine-14C in the rat. Br J Pharmacol 34:445–450.
Husain, M. A., Roberts, J. B., Thomas, B. H., Wilson, A. (1969). Metabolism and exretion of 3-hydroxyphenyltrimethylammo-nium and neostigmine. Br J Pharmacol 35:344–350.
Ichimaru, S., Kudo, Y., Kawakita, Y., Shimada, O. (1984). Phase I study of KTH-497, a new benzodiazepine derivative. Clin Eval 12:15–42.
Iosifidou, E. G., Haagsma, N., Olling, M., Boon, J. H., Tanck, M. W. (1997). Residue study of mebendazole and its metabo-lites hydroxy-mebendazole and amino-mebendazole in eel (Anguilla anguilla) after bath treatment. Drug Metab Dispos 25: 317–320.
Ishikawa, T., Utoh, M., Sawada, N., Nishida, M., Fukase, Y., Sekiguchi, F., et al. (1998). Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharmacol 55:1091–1098.
Kahns, A. H., Bundgaard, H. (1991). N-acyl derivatives as prodrugs forms for amides: chemical stability and enzymatic hydrolysis of various N-acyl and N-alkoxycarbonyl amide derivatives. Int J Pharm 71:31–43.
Kahns, A. H., Bundgaard, H. (1991). Prodrugs of peptides. 14. Bioreversible derivatization of the tyrosine phenol group to effect protection of tyrosyl peptides against [alpha]-chymotrypsin. Int J Pharm 76:99–112.
Kaiser, D. G., Shaw, S. R. (1974). GLC determination of chlorphenesin carbamate in serum. J Pharm Sci 63:1094–1097.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 585
Kaneda, N., Nagata, H., Furuta, T., Yokokura, T. (1990). Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 50:1715–1720.
Kapetanovic, I. M., Torchin, C. D., Thompson, C. D., Miller, T. A., McNeilly, P. J., Macdonald, T. L., et al. (1998). Potentially reactive cyclic carbamate metabolite of the antiepileptic drug felbamate produced by human liver tissue in vitro. Drug Metab Dispos 26:1089–1095.
Kassahun, K., Skordos, K., McIntosh, I., Slaughter, D., Doss, G. A., Baillie, T. A., et al. (2005). Zafirlukast metabolism by cyto-chrome P450 3A4 produces an electrophilic alpha,beta-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme. Chem Res Toxicol 18: 1427–1437.
Katchen, B., Cramer, J., Chung, M., Gural, M., Hilbert, J., Luc, V., et al. (1985). Disposition of 14C-SCH 29851 in humans. Ann Allerg 55:393.
Kaye, B., Offerman, J. L., Reid, J. L., Elliott, H. L., Hillis, W. S. (1984). A species difference in the presystemic metabolism of carbazeran in dog and man. Xenobiotica 14:935–945.
Kaye, B., Rance, D. J., Waring, L. (1985). Oxidative metabolism of car-bazeran in vitro by liver cytosol of baboon and man. Xenobiotica 15:237–242.
Kennedy, K. A., Sligar, S. G., Polomski, L., Sartorelli, A. C. (1982). Metabolic activation of mitomycin C by liver microsomes and nuclei. Biochem Pharmacol 31:2011–2016.
Kirdani, R. Y., Mittelman, A., Murphy, G. P., Sandberg, A. A. (1975). Studies on phenolic steroids in human subjects. XIV. Fate of a nitrogen mustard of estradiol-17beta. J Clin Endocrinol Metab 41:305–318.
Kirdani, R. Y., Murphy, G. P., Sandberg, A. A. (1977). Studies on a nitro-gen mustard of estradiol in dogs and rats. Proc Soc Exp Biol Med 155:94–98.
Kitamura, S., Fukushi, I., Miyawaki, T., Kawamura, M., Terashita, E., Naka, T. (2001). Orally active GPIIb/IIIa antagonists: synthesis and biological activities of masked amidines as prodrugs of 2-[(3S)-4. Chem Pharm Bull (Tokyo) 49:268–277.
Kleber, J. W., Bechtol, L. D., Brunson, M. K., Chernish, S. M. (1977). GLC determination of ethinamate and its hydroxy derivative in biological fluids. J Pharm Sci 66:992–994.
Klemm, W., Morgenroth, U., Joram, U., Rodionov, A. P. (1985). Pharmacokinetics and metabolism of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzylhydro chloride (Bonnecor, AWD 19-166, GS 015) in the rat. Pharmazie 40:864–867.
Kohara, Y., Imamiya, E., Kubo, K., Wada, T., Inada, Y., Naka, T. (1995). A new class of angiotensin II receptor antagonists with a novel acidic bioisostere. Bioorg Med Chem Lett 5:1903–1908.
Kohara, Y., Kubo, K., Imamiya, E., Wada, T., Inada, Y., Naka, T. (1996). Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J Med Chem 39:5228–5235.
Koudriakova, T., Iatsimirskaia, E., Utkin, I., Gangl, E., Vouros, P., Storozhuk, E., et al. (1998). Metabolism of the human immu-nodeficiency virus protease inhibitors, indinavir and ritonavir, by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 26:552–561.
Kumar, G. N., Rodrigues, A. D., Buko, A. M., Denissen, J. F. (1996). Cytochrome P450–mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277:423–431.
Lang, W., Mao, J., Doyle, T. W., Almassian, B. (2000a). Isolation and identification of urinary metabolites of porfiromycin in dogs and humans. Drug Metab Dispos 28:899–904.
Lang, W., Mao, J., Wang, Q., Niu, C., Doyle, T. W., Almassian, B. (2000b). Isolation and identification of metabolites of porfiro-mycin formed in the presence of a rat liver preparation. J Pharm Sci 89:191–198.
Lang, W., Caldwell, G. W., Masucci, J. A. (2005). Evaluation of the effect of oxygen exposure on human liver microsomal metabolism of mitomycin C in the presence of glutathione using liquid chro-matography-quadrupole time of flight mass spectrometry. Anal Biochem 343:268–276.
Li, L. H., DeKoning, T. F., Kelly, R. C., Krueger, W. C., McGovren, J. P., Padbury, G. E., et al. (1992). Cytotoxicity and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue. Cancer Res 52:4904–4913.
Li, W., Zhang, D., Wang, L., Zhang, H., Cheng, P. T., Zhang, D., et al. (2006). Biotransformation of carbon-14–labeled muraglitazar in male mice: interspecies difference in metabolic pathways leading to unique metabolites. Drug Metab Dispos 34:807–820.
Lindberg, C., Roos, C., Tunek, A., Svensson, L. A. (1989). Metabolism of bambuterol in rat liver microsomes: identification of hydroxy-lated and demethylated products by liquid chromatography mass spectrometry. Drug Metab Dispos 17:311–322.
Lokiec, F., du Sordier, B. M., Sanderink, G. J. (1996). Irinotecan (CPT-11) metabolites in human bile and urine. Clin Cancer Res 2:1943–1949.
Lu, X. L., Yang, S. K. (1993). Enantioselective metabolism of camazepam by rat liver microsomes. J Pharm Biom Anal 11:1189–1196.
Ludwig, B. J., Douglas, J. F., Powell, L. S., Meyer, M., Berger, F. M. (1961). Structures of the major metabolites of meprobamate. J Med Pharm Chem 3:53–64.
Mannens, G. S., Hendrickx, J., Janssen, C. G., Chien, S., Van Hoof, B., Verhaeghe, T., et al. (2007). The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethan-ediol, [1-2-chlorophenyl]-2-carbamate, [S]-) in humans. Drug Metab Dispos 35:554–565.
Mamidi, R. N., Mannens, G., Annaert, P., Hendrickx, J., Goris, I., Bockx, M., et al. (2007). Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs. Drug Metab Dispos 35:566–575.
Marriner, S. E., Bogan, J. A. (1980). Pharmacokinetics of albendazole in sheep. Am J Vet Res 41:1126–1129.
Maryanoff, B. E., McComsey, D. F., Costanzo, M. J., Yabut, S. C., Lu, T., Player, M. R., et al. (2006). Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa. Chem Biol Drug Des 68:29–36.
Mathijssen, R. H., van Alphen, R. J., Verweij, J., Loos, W. J., Nooter, K., Stoter, G., et al. (2001). Clinical pharmacokinetics and metabo-lism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194.
Maurin, M. B., Rowe, S. M., Blom, K., Pierce, M. E. (2002). Kinetics and mechanism of hydrolysis of efavirenz. Pharm Res 19:517–521.
Mayo, B. C., Brodie, R. R., Chasseaud, L. F., Hawkins, D. R. (1978). Biotransformation of methyl 5-cyclopropylcarbonyl-2-benzimi-dazolecarbamate (ciclobendazole) in rats and dogs. Drug Metab Dispos 6:518–527.
McKellar, Q. A., Gokbulut, C., Muzandu, K., Benchaoui, H. (2002). Fenbendazole pharmacokinetics, metabolism, and potentiation in horses. Drug Metab Dispos 30:1230–1239.
McMahon, R. E. (1958). The in vivo hydroxylation of 1-ethynylcy-clohexyl carbamate. J Am Chem Soc 80:411–414.
McNeilly, P. J., Torchin, C. D., Anderson, L. W., Kapetanovic, I. M., Kupferberg, H. J., Strong, J. M. (1997). In vitro glucuronidation of D-23129, a new anticonvulsant, by human liver microsomes and liver slices. Xenobiotica 27:431–441.
Mendes, E., Furtado, T., Neres, J., Iley, J., Jarvinen, T., Rautio, J., et al. (2002). Synthesis, stability, and in vitro dermal evaluation of aminocarbonyloxymethyl esters as prodrugs of carboxylic acid agents. Bioorg Med Chem 10:809–816.
Merino, G., Molina, A. J., Garcia, J. L., Pulido, M. M., Prieto, J. G., Alvarez, A. I. (2003). Effect of clotrimazole on microsomal metab-olism and pharmacokinetics of albendazole. J Pharm Pharmacol 55:757–764.
Meuldermans, W. E., Hurkmans, R. M., Lauwers, W. F., Heykants, J. J. (1976). The in vitro metabolism of mebendazole by pig, rat, and dog liver fractions. Eur J Drug Metab Pharmacokinet 1:35–40.
Miwa, M., Ura, M., Nishida, M., Sawada, N., Ishikawa, T., Mori, K., et al. (1998). Design of novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281.
Montesissa, C., Stracciari, J. M., Fadini, L., Beretta, C. (1989). Comparative microsomal oxidation of febantel and its metabo-lite fenbendazole in various animal species. Xenobiotica 19: 97–100.
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
586 F. Vacondio et al.
Morino, A., Nakamura, A., Nakanishi, K., Tatewaki, N., Sugiyama, M. (1985). Species differences in the disposition and metabolism of camazepam. Xenobiotica 15:1033–1043.
Moroni, P., Buronfosse, T., Longin-Sauvageon, C., Delatour, P., Benoit, E. (1995). Chiral sulfoxidation of albendazole by the flavin ade-nine dinucleotide-containing and cytochrome P450–dependent monooxygenases from rat liver microsomes. Drug Metab Dispos 23:160–165.
Møss, J., Buur, A., Bundgaard, H. (1990). Prodrugs of peptides. 8. In vitro study of intestinal metabolism and penetration of thyro-tropin-releasing hormone (TRH) and its prodrugs. Int J Pharm 66:183–191.
Muir, W. W., Sams, R. A., Ashcraft, S. (1984). Pharmacologic and phar-macokinetic properties of methocarbamol in the horse. Am J Vet Res 45:2256–2260.
Muller, T. H., Weisenberger, H., Brickl, R., Narjes, H., Himmelsbach, F., Krause, J. (1997). Profound and sustained inhibition of plate-let aggregation by fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, lefradafiban, in men. Circulation 96:1130–1138.
Murray, M., Hudson, A. M., Yassa, V. (1992). Hepatic microsomal metabolism of the anthelmintic benzimidazole, fenbendazole: enhanced inhibition of cytochrome P450 reactions by oxidized metabolites of the drug. Chem Res Toxicol 5:60–66.
Mutlib, A. E., Chen, H., Nemeth, G. A, Markwalder, J. A., Seitz, S. P., Gan, L. S., et al. (1999a). Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrom-etry and high-field NMR: species differences in the metabolism of efavirenz. Drug Metab Dispos 27:1319–1333.
Mutlib, A. E., Chen, H., Nemeth, G., Gan, L-S., Christ, D. D. (1999b). Liquid chromatography/mass spectrometry and high-field nuclear magnetic resonance characterization of novel mixed diconjugates of the non-nucleoside human immunodeficiency virus-1 reverse transcriptase inhibitor, efavirenz. Drug Metab Dispos 27:1045–1056.
Mutlib, A. E., Gerson, R. J., Meunier, P. C., Haley, P. J., Chen, H., Gan, L. S., et al. (2000). The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol Appl Pharmacol 169:102–113.
Nakamura, A., Tatewaki, N., Morino, A., Sugiyama, M. (1986). The met-abolic fate of camazepam in rats. Xenobiotica 16:1079–1089.
Naitoh, T., Kakiki, M., Kozaki, T., Mishima, M., Yuzuriha, T., Horie, T. (1997a). Identification of the metabolites of a new oxazolidinone MAO-A inhibitor in rat. Xenobiotica 27:1071–1089.
Naitoh, T., Mishima, M., Kawaguchi, S., Matsui, K., Andoh, T., Kagei, K., et al. (1997b). Absorption, distribution, metabolism, and excretion of a new, 14C-labelled oxazolidinone MAO-A inhibitor in rat and dog. Xenobiotica 27:1053–1070.
Namour, F., Wessels, D. H., Pascual, M. H., Reynolds, D., Sultan, E., Lenfant, B. (2001). Pharmacokinetics of the new ketolide telithro-mycin (HMR 3647) administered in ascending single and multi-ple doses. Antimicrob Agents Chemother 45:170–175.
Nyberg, L., Rosenborg, J., Weibull, E., Jonsson, S., Kennedy, B. M., Nilsson, M. (1998). Pharmacokinetics of bambuterol in healthy subjects. Br J Clin Pharmacol 45:471–478.
Obermeier, K., Niebch, G., Thiemer, K. (1985). Pharmacokinetics and biotransformation of the analgesic flupirtine in the rat and dog. Arzneim-Forsch Drug Res 35:60–67.
Ohkawa, T., Goto, S., Miki, S., Sato, A., Kuroda, T., Iwatani, K., et al. (1998). Structural determination of metabolites of S-1153, a new, potent, non-nucleoside, anti-HIV agent in rat liver microsomes. Xenobiotica 28:877–886.
Ouattara, M., Wein, S., Calas, M., Hoang, Y. V., Vial, H., Escale, R. (2007). Synthesis and antimalarial activity of new 1,12-bis(N,N’-acetamidinyl)dodecane derivatives. Bioorg Med Chem Lett 17:593–596.
Pan, S. S., Andrews, P. A., Glover, C. J., Bachur, N. R. (1984). Reductive activation of mitomycin C and mitomycin C metabolites cata-lyzed by NADPH-cytochrome P-450 reductase and xanthine oxi-dase. J Biol Chem 259:959–966.
Parker, R. J., Hartman, N. R., Roecklein, B. A., Mortko, H., Kupferberg, H. J., Stables, J., et al. (2005). Stability and comparative metab-olism of selected felbamate metabolites and postulated
fluorofelbamate metabolites by postmitochondrial suspensions. Chem Res Toxicol 18:1842–1848.
Parli, C. J., Wang, N., McMahon, R. E. (1972). Effects of microsomal mono-oxygenase inhibitors upon the in vivo metabolism and duration of action of 1-ethynylcyclohexyl carbamate. J Pharmacol Exp Ther 180:791–796.
Pelizzi, N., Puccini, P., Riccardi, B., Acerbi, D., Catinella, S. (2003). Characterization of ganstigmine metabolites in hepatocytes by low- and high-resolution mass spectrometry coupled with liquid chromatography. Rapid Commun Mass Spectrom 17:1691–1698.
Penicaut, B., Maucein, P., Maissonneuve, H., Rossignol, J. F. (1983). Pharmacokinetics and metabolism of albendazole in humans. Bull Soc Path Ex 76:698–708.
Perret, C., Lenfant, B., Weinling, E., Wessels, D. H., Scholtz, H. E., Montay, G., et al. (2002). Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers. Chemotherapy 48:217–223.
Petersen, M. B., Friis, C. (2000). Pharmacokinetics of fenbendazole following intravenous and oral administration to pigs. Am J Vet Res 61:573–576.
Phillips, B. M., Miya, T. S., Yim, G. K. (1962). Studies on the mecha-nism of meprobamate tolerance in the rat. J Pharmacol Exp Ther 135:223–239.
Pieniaszek, H. J., Davidson, A. F., McEntegart, C. M., Quon, C. Y., Sampliner, R. E., Mayersohn, M. (1994). The effect of hepatic disease on the disposition of moricizine in humans. Biopharm Drug Dispos 15:243–252.
Pieniaszek, H. J., Davidson, A. F., Chaney, J. E., Shum, L., Robinson, C. A., Mayersohn, M. (1999). Human moricizine metabolism.II. Quantification and pharmacokinetics of plasma and urinary metabolites. Xenobiotica 29:945–955.
Piwinski, J. J., Wong, J. K., Chan, T-M., Green, M. J., Ganguly, A. K. (1990). Hydroxylated metabolites of loratadine: an exemple of conformational diasteroisomers due to atropisomerism. J Org Chem 55:3341–3350.
Polinsky, R. J. (1998). Clinical pharmacology of rivastigmine: a new generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther 20:634–647.
Rahmathullah, S. M., Hall, J. E., Bender, B. C., McCurdy, D. R., Tidwell, R. R., Boykin, D. W. (1999). Prodrugs for amidines: synthesis and anti–Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan. J Med Chem 42:3994–4000.
Raito, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., et al. (2008). Prodrugs: design and clinical applications. Nat Rev Drug Discov 7:255–270.
Ramanathan, R., Alvarez, N., Su, A. D., Chowdhury, S., Alton, K., Stauber, K., Patrick, J. (2005). Metabolism and excretion of lorata-dine in male and female mice, rats, and monkeys. Xenobiotica 35:155–189.
Ramanathan, R., Reyderman, L., Kulmatycki, K., Su, A. D., Alvarez, N., Chowdhury, S. K., et al. (2007). Disposition of loratadine in healthy volunteers. Xenobiotica 37:753–769.
Rawden, H. C., Kokwaro, G. O., Ward, S. A., Edwards, G. (2000). Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Br J Clin Pharmacol 49:313–322.
Rehse, K., Bade, S., Harsdorf, A., Clement, B. (1997). New NO-donors with antithrombotic and vasodilating activities, Part 17. Arylazoamidoximes and 3-arylazo-1,2,4-oxadiazol-5-ones. Arch Pharm (Weinheim) 330:392–398.
Reigner, B., Blesh, K., Weidekamm, E. (2001). Clinical pharmacokinet-ics of capecitabine. Clin Pharmacokinet 40:85–104.
Richards, L. E., Pieniaszek, H. J., Shatzmiller, S., Page, G. O., Blom, K. F., Read, J. M., et al. (1997). Human moricizine metabolism. I. Isolation and identification of metabolites in human urine. Xenobiotica 27:217–229.
Riggs, J. R., Kolesnikov, A., Hendrix, J., Young, W. B., Shrader, W. D., Vijaykumar, D., et al. (2006). Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability. Bioorg Med Chem Lett 16:2224–2228.
Rivara, M., Vacondio, F., Silva, C., Zuliani, V., Fantini, M., Bordi, F., et al. (2008). Synthesis and stability in biological media of 1H-
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
Hydrolysis of carbamates: qualitative structure-metabolism relationships 587
imidazole-1-carboxylates of ROS203, an antagonist of the hista-mine H3 receptor. Chem Biodivers 5:140–152.
Rivory, L. P., Robert, J. (1995). Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after admin-istration of the camptothecin derivative irinotecan. Cancer Chemother Pharmacol 36:176–179.
Rivory, L. P., Bowles, M. R., Robert, J., Pond, S. M. (1996). Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10- hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 52:1103–1111.
Roberts, J. B., Thomas, B. H., Wilson, A. (1966). Excretion and metab-olism of oral neostigmine-14C in the rat. Biochem Pharmacol 15:71–75.
Roberts, J. B., Thomas, B. H., Wilson, A. (1968). Metabolism of neostig-mine in vitro. Biochem Pharmacol 17:9–12.
Roecklein, B. A., Sacks, H. J., Mortko, H., Stables, J. (2007). Fluorofelbamate. Neurotherapeutics 4:97–101.
Rolin, S., Souhaili-el Amri, H., Batt, A. M., Levy, M., Bagrel, D., Siest, G. (1989). Study of the in vitro bioactivation of albendazole in human liver microsomes and hepatoma cell lines. Cell Biol Toxicol 5:1–14.
Roller, S. G., Dieckhaus, C. M., Santos, W. L., Sofia, R. D., Macdonald, T. L. (2002). Interaction between human serum albumin and the felbamate metabolites 4-hydroxy-5-phenyl-[1,3]oxazinan-2-one and 2-phenylpropenal. Chem Res Toxicol 15:815–824.
Romanyshyn, L. A., Wichmann, J. K., Kucharczyk, N., Sofia, R. D. (1994). Simultaneous determination of felbamate and three metabolites in human plasma by high-performance liquid chro-matography. Ther Drug Monit 16:83–89.
Rosenblum, C., Trenner, N. R., Buhs, R. P., Hiremath, C. B., Koniuszy, F. R., Wolf, D. E. (1972). Metabolism of ronidazole (1-methyl-5-nitroimidazol-2-ylmethyl carbamate). J Agric Food Chem 20:360–371.
Rosing, H., Lustig, V., van Warmerdam, L. J., Huizing, M. T., ten Bokkel Huinink, W. W., Schellens, J. H., et al. (2000). Pharmacokinetics and metabolism of docetaxel administered as a 1-hour intrave-nous infusion. Cancer Chemother Pharmacol 45:213–218.
Rovei, V., Mitchard, M., Strolin Benedetti, M., Kendall, M. J. (1984). Pharmacokinetic and relative bioavailability studies of cimoxa-tone in humans. Int J Clin Pharmacol Ther Toxicol 22:56–62.
Ryrfeldt, A., Nilsson, E., Tunek, A., Svensson, L. A. (1988). Bambuterol: uptake and metabolism in guinea pig isolated lungs. Pharm Res 5:151–155.
Sadler, B. M., Chittick, G. E., Polk, R. E., Slain, D., Kerkering, T. M., Studenberg, S. D., et al. (2001). Metabolic disposition and phar-macokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J Clin Pharmacol 41:386–396.
Sai, K., Kaniwa, N., Ozawa, S., Sawada, J. I. (2001). A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4. Drug Metab Dispos 29:1505–1513.
Sanchez, S., Small, J., Jones, D. G., McKellar, Q. A. (2003). Dexamethasone decreases plasma levels of the prochiral fen-bendazole and its chiral and achiral metabolites in sheep. Xenobiotica 33:731–742.
Sanghani, S. P., Quinney, S. K., Fredenburg, T. B., Davis, W. I., Murry, D. J., Bosron, W. F. (2004). Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxy-camptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxy-lesterase isoenzyme, CES3. Drug Metab Dispos 32:505–511.
Santos, A., Zanetta, S., Cresteil, T., Deroussent, A., Pein, F., Raymond, E., et al. (2000). Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 6:2012–2020.
Sargent, N. S., Upshall, D. G., Bridges, J. W. (1982a). The relationship between binding to cytochrome P-450 and metabolism of n-alkyl carbamates in isolated rat hepatocytes. Biochem Pharmacol 31:1309–1313.
Sargent, N. S., Wood, S. G., Upshall, D. G., Bridges, J. W. (1982b). The relationship between chemical structure and the in vivo metab-olism of an homologous series of n-alkyl carbamates. J Pharm Pharmacol 34:367–372.
Savidge, R. D., Bui, K. H., Birmingham, B. K., Morse, J. L., Spreen, R. C. (1998). Metabolism and excretion of zafirlukast in dogs, rats, and mice. Drug Metab Dispos 26:1069–1076.
Savolainen, J., Leppanen, J., Forsberg, M., Taipale, H., Nevalainen, T., Huuskonen, J., et al. (2000). Synthesis and in vitro/in vivo evalu-ation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone. Life Sci 67:205–216.
Schwartz, H. S. (1962). Pharmacology of mitomycin C. III. In vitro metabolism by rat liver. J Pharmacol Exp Ther 36:250–258.
Scott, C. A., Nowell, P. T., Wilson, A. (1962). An investigation of the metabolism of neostigmine in patients with myasthenia gravis. J Pharm Pharmacol 14:31T–33T.
Shi, J., Montay, G., Bhargava, V. O. (2005). Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial. Clin Pharmacokin 44:915–934.
Short, C. R., Barker, S. A., Flory, W. (1988a). Comparative drug metab-olism and disposition in minor species. Vet Hum Toxicol 30 (Suppl 1):2–8.
Short, C. R., Flory, W., Hsieh, L. C., Barker, S. A. (1988b). The oxida-tive metabolism of fenbendazole: a comparative study. J Vet Pharmacol Ther 11:50–55.
Singh, R., Chang, S. Y., Taylor, L. C. (1996). In vitro metabolism of a potent HIV-protease inhibitor (141W94) using rat, mon-key, and human liver S9. Rapid Commun Mass Spectrom 10: 1019–1026.
Slatter, J. G., Su, P., Sams, J. P., Schaaf, L. J., Wienkers, L. C. (1997). Bioactivation of the anticancer agent, CPT-11, to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactions. Drug Metab Dispos 25:1157–1164.
Slatter, J. G., Schaaf, L. J., Sams, J. P., Feenstra, K. L., Johnson, M. G., Bombardt, P. A., et al. (2000). Pharmacokinetics, metabolism and excretion of irinotecan (CPT-11) following i.v. infusion of [14C]CPT-11 in cancer patients. Drug Metab Dispos 28:423–433.
Slatter, J. G., Stalker, D. J., Feenstra, K. L., Welshman, I. R., Bruss, J. B., Sams, J. P., et al. (2001). Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects. Drug Metab Dispos 29:1136–1145.
Souhaili-El Amri, H., Fargetton, X., Delatour, P., Batt, A. M. (1987). Sulphoxidation of albendazole by the FAD-containing and cyto-chrome P-450 dependent mono-oxygenases from pig liver micro-somes. Xenobiotica 17:1159–1168.
Souhaili-El Amri, H., Mothe, O., Totis, M., Masson, C., Batt, A. M., Delatour, P., et al. (1988). Albendazole sulfonation by rat liver cytochrome P-450c. J Pharmacol Exp Ther 246:758–764.
Sparreboom, A., Van Tellingen, O., Scherrenburg, E. J., Boesen, J. J., Huizing, M. T., Nooijen, W. J., et al. (1996). Isolation, purifica-tion, and biological activity of major docetaxel metabolites from human feces. Drug Metab Dispos 24:655–658.
Srivastava, P., Sharma, P., Lal, J., Dikshit, D. K., Madhusudanan, K. P., Gupta, R. C. (2004). Metabolism of CDRI-85/92, a new potent anti-ulcer agent, involving cis-trans conversion. Drug Metab Drug Interact 20:57–75.
Stangier, J., Eriksson, B. I., Dahl, O. E., Ahnfelt, L., Nehmiz, G., Stahle, H., et al. (2005). Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 45:555–563.
Stark, H., Krause, M., Rouleau, A., Garbarg, M., Schwartz, J-C., Schunack, W. (2001). Enzyme-catalyzed prodrug approaches for the histamine H3-receptor agonist, (R)-α-methylhistamine. Bioorg Med Chem 9:191–198.
Stefek, M., Bezek, S. (1985). Hepatic uptake and metabolism of penta-caine: a study with microsomes, hepatocytes, and perfused livers of rats. Xenobiotica 15:805–812.
Stefek, M., Benes, L., Kovacik, V. (1986). Identification of in vitro rat metabolites of pentacaine, a carbanilate local anesthetic, by gas chromatography/mass spectrometry. Biomed Environm Mass Spectrom 13:193–198.
Svensson, L. A., Tunek, A. (1988). The design and bioactivation of presystemically stable prodrugs. Drug Metab Rev 19:165–194.
Takayanagui, O. M., Bonato, P. S., Dreossi, S. A., Lanchote, V. L. (2002). Enantioselective distribution of albendazole metabolites in
Dru
g M
etab
olis
m R
evie
ws
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Can
tona
le e
t Uni
vers
itair
e on
09/
30/1
0Fo
r pe
rson
al u
se o
nly.
588 F. Vacondio et al.
cerebrospinal fluid of patients with neurocysticercosis. Br J Clin Pharmacol 54:125–130.
Tanino, T., Ogiso, T., Iwaki, M., Tanabe, G., Muraoka, O. (1998). Enhancement of oral bioavailability of phenytoin by esterifi-cation and in vitro hydrolytic characteristics of prodrugs. Int J Pharm 163:91–102.
Tanayama, S., Fujita, T., Shirakawa, Y., Suzuoki, Z. (1970). Metabolic fate of 5-ethoxycarbonyl-3-morpholinosydnonimine (SIN-10). 1. Absorption, excretion, and tissue distribution in rats and mice. Jpn J Pharmacol 20:413–423.
Tanayama, S., Nakai, Y., Fujita, T., Sukuoki, Z., Imashiro, Y., Masuda, K. (1974). Biotransformation of molsidomine (N-ethoxycarbonyl-3-morpholinosyndonimine), a new antianginal agent in rats. Xenobiotica 4:175–191.
Testa, B., Mayer, J. M. (2003). Hydrolysis in drug and prodrug metab-olism—chemistry, biochemistry, and enzymology. Weinheim, Germany: Wiley-VCH.
Testa, B. (2007). Prodrug objectives and design. In: Testa, B., van de Waterbeemd, H. (Eds.), ADME-Tox approaches, vol 5 (pp 1009–1041). In: Taylor, J. B., Triggle, D. J. (Eds.), Comprehensive medicinal chemistry II. Oxford, UK: Elsevier.
Testa, B. (2009). Prodrugs: bridging pharmacodynamic/pharmacoki-netic gaps. Curr Opin Chem Biol 13:338–344.
Testa, B., Krämer, S. D. (2009). The biochemistry of drug metabo-lism—an introduction. Part 5: metabolism and bioactivity. Chem Biodivers 6:591–684.
Thomsen, K., Bundgaard, H. (1993). Cyclization-activated phenyl car-bamate prodrug forms for protecting phenols against first-pass metabolism. Int J Pharm 91:39–49.
Thomsen, K., Strom, F., Sforzini, B. V., Begtrup, M., Mork, N. (1994). Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism. Int J Pharm 112:143–152.
Thompson, C. D., Kinter, M. T., Macdonald, T. L. (1996). Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate. Chem Res Toxicol 9:1225–1229.
Thompson, C. D., Gulden, P. H., Macdonald, T. L. (1997). Identification of modified atropaldehyde mercapturic acids in rat and human urine after felbamate administration. Chem Res Toxicol 10:457–462.
Thompson, C. D., Barthen, M. T., Hopper, D. W., Miller, T. A., Quigg, M., Hudspeth, C., et al. (1999). Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids. Epilepsia 40:769–776.
Thompson, C. D., Miller, T. A., Barthen, M. T., Dieckhaus, C. M., Sofia, R. D., Macdonald, T. L. (2000). The synthesis, in vitro reactivity, and evidence for formation in humans of 5-phenyl-1,3-oxazi-nane-2,4-dione, a metabolite of felbamate. Drug Metab Dispos 28:434–439.
Tréluyer, J. M., Bowers, G., Cazali, N., Sonnier, M., Rey, E., Pons, G., et al. (2003). Oxidative metabolism of amprenavir in the human liver. Effect of the CYP3A maturation. Drug Metab Dispos 31:275–281.
Tsukamoto, Y., Kato, Y., Ura, M., Horii, I., Ishitsuka, H., Kusuhara, H., et al. (2001). A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans: the mech-anism for tumor-selective accumulation of 5-FU. Pharm Res 18:1190–1202.
Tomasz, M., Lipman, R. (1981). Reductive metabolism and alkylat-ing activity of mytomycin C induced by rat liver microsomes. Biochemistry 20:5056–5061.
Tse, F. L., Laplanche, R. (1998). Absorption, metabolism, and disposi-tion of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration. Pharm Res 15:1614–1620.
Tunek, A., Levin, E., Svensson, L-Å,. (1988a). Hydrolysis of 3H-bam-buterol, a carbamate prodrug of terbutaline, in blood from humans and laboratory animals in vitro. Biochem Pharmacol 37:3867–3876.
Tunek, A., Svensson, L. A. (1988b). Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood. Drug Metab Dispos 16:759–764.
Vacondio, F., Silva, C., Lodola, A., Fioni, A., Rivara, S., Duranti, A., et al. (2009). Structure-property relationships of a class of carbamate-based fatty acid amide hydrolase (FAAH) inhibitors: chemical and biological stability. ChemMedChem 4:1495–1504.
VandenHeuvel, W. J., Wolf, D. E., Arison, B. H., Buhs, R. P., Carlin, J. R., Ellsworth, R. L., et al. (1978). Urinary metabolites of camben-dazole. J Agric Food Chem 26:1357–1364.
van Tellingen, O., Nooijen, W. J., Schaaf, L. J., van der Valk, M., van Asperen, J., Henrar, R. E., et al. (1998a). Comparative pharmacol-ogy of the novel cyclopropylpyrroloindole-prodrug carzelesin in mice, rats, and humans. Cancer Res 58:2410–2416.
van Tellingen, O., Punt, C. J., Awada, A., Wagener, D. J., Piccart, M. J., Groot, Y., et al. (1998b). A clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study. Cancer Chemother Pharmacol 41:377–384.
Velik, J., Baliharova, V., Skalova, L., Szotakova, B., Wsol, V., Lamka, J. (2005). Liver microsomal biotransformation of albendazole in deer, cattle, sheep, and pig and some related wild breeds. J Vet Pharmacol Ther 28:377–384.
Vigroux, A., Bergon, M., Zedde, C. (1995). Cyclization-activated pro-drugs: N-(substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates based on ring-opened derivatives of active ben-zoxazolones and oxazolidinones as mutual prodrugs of aceta-minophen. J Med Chem 38:3983–3994.
Villaverde, C., Alvarez, A. I., Redondo, P., Voces, J., Del Estal, J. L., Prieto, J. G. (1995). Small intestinal sulphoxidation of albenda-zole. Xenobiotica 25:433–441.
Virkel, G., Lifschitz, A., Soraci, A., Sansinanea, A., Lanusse, C. (2000). Enantioselective liver microsomal sulphoxidation of albendazole in cattle: effect of nutritional status. Xenobiotica 30:381–393.
Virkel, G., Lifschitz, A., Sallovitz, J., Pis, A., Lanusse, C. (2004). Comparative hepatic and extrahepatic enantioselective sul-foxidation of albendazole and fenbendazole in sheep and cattle. Drug Metab Dispos 32:536–544.
Walkenstein, S. S., Knebel, C. M., Macmullen, J. A., Seifter, J. (1958). The excretion and distribution of meprobamate and its metabo-lites. J Pharmacol Exp Ther 123:254–258.
Wang, L, Zhang, D, Swaminathan, A, Xue, Y, Cheng, PT, Wu, S, et al. (2006). Glucuronidation as a major metabolic clearance path-way of 14C-labeled muraglitazar in humans: metabolic profiles in subjects with or without bile collection. Drug Metab Dispos 34:427–439.
Wanner, M. J., Melle, K., Koomen, G-J. (2004). Synthesis and anti-tumor activity of methyltriazene prodrugs simultaneously releasing DNA-methylating agents and the antiresistance drug O6-benzylguanine. J Med Chem 47:6875–6883.
Ward, B. A., Gorski, J. C., Jones, D. R., Hall, S. D., Flockhart, D. A., Desta, Z. (2003). The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: impli-cation for HIV/AIDS therapy and utility of efavirenz as a sub-strate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287–300.
Wei, G., Loktionova, N. A., Pegg, A. E., Moschel, R. C. (2005). Beta-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2′-deoxyguanosine. J Med Chem 48: 256–261.
Weller, T., Alig, L., Beresini, M., Blackburn, B., Bunting, S., Hadvary, P., et al. (1996). Orally active fibrinogen receptor antago-nists. 2. Amidoximes as prodrugs of amidines. J Med Chem 39:3139–3147.
Wilson, I. D., Watson, K. V., Troke, J., Illing, H. P., Fromson, J. M. (1986). The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in laboratory animals. Xenobiotica 16:1117–1128.
Wilson, I. D., Fromson, J. M., Illing, H. P., Schraven, E. (1987). The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in man. Xenobiotica 17:93–104.
Wolf, D. E., VandenHeuvel, J. A., Tyler, T. R., Walker, R. W., Koniuszy, F. R., Gruber, V., et al. (1980). Identification of a glutathione con-jugate of cambendazole formed in the presence of liver micro-somes. Drug Metab Dispos 8:131–136.
Wynalda, M. A., Hauer, M. J., Wienkers, L. C. (2000). Oxidation of the novel oxazolidinone antibiotic linezolid in human liver micro-somes. Drug Metab Dispos 28:1014–1017.
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Hydrolysis of carbamates: qualitative structure-metabolism relationships 589
Xie, M., Yu, D., Wu, M., Xue, B., Yan, B. (2003). Mouse liver and kidney carboxylesterase (M-LK) rapidly hydrolyzes antitumor prodrug irinotecan and the N-terminal three quarter sequence deter-mines substrate selectivity. Drug Metab Dispos 31:21–27.
Yang, J. M., Chan, K. (1995). Isolation and characterization of sulphox-idation metabolites of moricizine in rat and human biological fluids. Meth Find Exp Clin Pharmacol 17:415–421.
Yang, J. T., Adusumalli, V. E., Wong, K. K., Kucharczyk, N., Sofia, R. D. (1991). Felbamate metabolism in the rat, rabbit, and dog. Drug Metab Dispos 19:1126–1134.
Yang, J. T., Morris, M., Wong, K. K., Kucharczyk, N., Sofia, R. D. (1992). Felbamate metabolism in pediatric and adult Beagle dogs. Drug Metab Dispos 20:84–88.
Yumibe, N., Huie, K., Chen, K. J., Clement, R. P., Cayen, M. N. (1995). Identification of human liver cytochrome P450s involved in the microsomal metabolism of the antihistaminic drug loratadine. Int Arch Allerg Immunol 107:420.
Yumibe, N., Huie, K., Snow, M., Clement, R. P., Cayen, M. N. (1996). Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine, loratadine. Biochem Pharmacol 51:165–172.
Zhang, D., Zhang, H., Aranibar, N., Hanson, R., Huang, Y., Cheng, P. T., et al. (2006). Structural elucidation of human oxidative metabolites of muraglitazar: use of microbial bioreactors in the biosynthesis of metabolite standards. Drug Metab Dispos 34: 267–280.
Zhang, D., Wang, L., Chandrasena, G., Ma, L., Zhu, M., Zhang, H., et al. (2007a). Involvement of multiple cytochrome P450 and UDP-glucuronosyltransferase enzymes in the in vitro metabolism of muraglitazar. Drug Metab Dispos 35:139–149.
Zhang, D., Wang, L., Raghavan, N., Zhang, H., Li, W., Cheng, P. T., et al. (2007b). Comparative metabolism of radiolabeled muraglitazar in animals and humans by quantitative and qualitative metabo-lite profiling. Drug Metab Dispos 35:150–167.
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