Pharmacokinetics of the thiazide diuretics
-
Upload
peter-g-welling -
Category
Documents
-
view
257 -
download
5
Transcript of Pharmacokinetics of the thiazide diuretics
BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 7 , 501-535 (1986)
REVIEW ARTICLE
PHARMACOKINETICS OF THE THIAZIDE DIURETICS
PETER G . WELLING
Pharmaceutical Research Division, Warner- Lambert Company, 2800 Plymouth Road, Ann Arbor, M I 48105, U.S.A.
KEY WORDS Thiazides Pharmacokinetics Assay Interactions Review
INTRODUCTION
The first thiazide diuretic was discovered as part of a systematic research programme to develop drugs which increase renal excretion of sodium and chloride ions. Initial studies in this programme focused on inhibition of carbonic anhydrase by sulfonamides. Derivatization of one compound chlorodisulfamoylaniline gave rise to a novel compound with a ben- zothiadiazine nucleus. ',* This compound, subsequently named chlor- othiazide, had a diuretic action based on a direct effect on renal tubular transport of sodium and chloride that was independent of any action on carbonic anhydrase.3 The effectiveness of chlorothiazide in the management of hypertension was first announced in 1957.4-5 The mechanism of action proposed for chlorothiazide appears to be common to all drugs of this class and includes increased excretion of potassium.
Although their effects are known to be localized at the early portion of the distal renal tubule,6 the mechanism by which the thiazide diuretics increase urinary excretion of sodium and chloride ions is not completely understood, nor is the precise mechanism(s) by which the saluretic effect lowers blood p r e ~ s u r e . ~
Since the discovery of chlorothiazide, many other drugs of this class have been described that have greater potency than the parent compound. However, all thiazides appear to have parallel dose response curves and similar maximum chloruretic effects.3 This is consistent with a similar mechanism of action. Thus the various compounds differ in the amount of drug required to achieve a given effect, but not necessarily in the optimal therapeutic response.
0142-2782/86/060501-35$17.50 @ 1986 by John Wiley & Sons, Ltd.
Received April 1986
502 PETER G . WELLING
CHEMICAL AND PHYSICAL PROPERTIES
Thiazide diuretics are derivatives of 1,2,4-benzothiadiazine-l,l-dioxide. Thus, the name ‘benzothiadiazides’ or ‘thiazides’. Their structures are given in Table 1. All compounds have the common benzothiadiazine nucleus, either in the reduced or oxidized form at positions 3 and 4, with different substituents at positions 2, 3, or 6. The daily dosage ranges (where available), also given in Table 1, demonstrate the wide range in potency of other thiazides relative to the parent chlorothiazide.
Physical properties of the thiazide diuretics are given in Table 2. Their molecular weights and melting points vary over a fairly narrow range, and
Table 1. Structures of thiazide diuretics
Name Structure Daily dose range (mg/day)
Benzthiazide
Chlorothiazide UZNSOZ )$ji CI
HzNS02
CI
Cyclopenthiazide
25-100
500-2000
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 503
Cyclothiazide
H ydrochlorothiazide
Hydroflumethiazide 25-200
HENSO*
CI
Methyclothiazide 2.5-10
H
Polythiazide 1-4
HzNSO,
CI
Trichlormethiazide 2-8
H
they are generally characterized by low aqueous solubility. As weak acids they are more soluble in alkali, often accompanied by degradation.
MARKETED PRODUCTS
The enormous number of marketed products that contain thiazide compounds, either alone or in combination with other antihypertensive
504 PETER G . WELLING
Table 2. Physical chemistry of thiazide diuretics
Molecular Solubility Melting weight point (")
Bemetizide 402 V. slightly soluble in water
Soluble in alcohol, acetone
Soluble in alkali
water Soluble in alkali
Bendroflumethiazide 42 1 Insoluble in water 221-223
Benzthiazide 432 Insoluble in water 238-239
Chlorothiazide 296 Soluble 0.4 mg ml-' in -345
Cyclopenthiazide 380 - 230 Cyclothiazide 390 Insoluble in water 2 17-225
Soluble in acetone, methanol
Soluble in alkali
water Soluble in alkali
Slightly soluble in ethanol, methanol
Soluble in methanol
ter, 21 mgml-' in ethanol
Hydrochlorothiazide 298 Insoluble in water 273-275
Hydroflumethiazide 33 1 Soluble 0.3 mg ml-' in 272-273
Methyclothiazide 360 V. slightly soluble in water -220
Polythiazide 440 Insoluble in water 207-217
Trichlormethiazide 381 Soluble 0.8 mg ml-' in wa- 274
agents, is illustrated in Table 3. Despite their low aqueous solubility all agents are marketed in oral tablets or capsules, and they are generally but not always well absorbed from the oral route.
PHARMACOKINETICS
Despite their extensive use for many years for the treatment of hypertension, the thiazides are better characterized by what is not known about their pharmacokinetics than by what is known. The pharmacokinetics of the more commonly prescribed agents chlorothiazide, hydrochlorothiazide, bendrof- lumethiazide, and hydroflumethiazide have been reasonably well characte- rized. However, information on the other compounds is fragmentary. Even for those compounds for which a reasonable amount of information is
Tab
le 3
. M
arke
ted
form
s of
thi
azid
e di
uret
ics
in th
e U
.S.A
.
Com
poun
d T
rade
Nam
e C
ompa
ny
Dos
age
Form
St
reng
th
Ben
drof
lum
ethi
azid
e B
endr
oflu
met
hiaz
ide
with
R
auw
olfia
B
endr
oflu
met
hiaz
ide
with
N
adol
ol
Ben
zthi
azid
e
Chl
orot
hiaz
ide
Chl
orot
hiaz
ide
Sodi
um
Chl
orot
hiaz
ide
with
M
ethy
ldop
a C
hlor
othi
azid
e w
ith R
e-
serp
i n e
Cyc
loth
iazi
de
Nat
uret
in
Rau
zide
Cor
zide
Aqu
atag
E
xna
Hyd
rex
Diu
ril
SK-C
hlor
othi
azid
e C
hlor
othi
azid
e C
hlor
othi
azid
e C
hlor
othi
azid
e D
iuril
A
ldoc
lor
Diu
pres
Anh
ydro
n
Squi
bb
Squi
bb
Squi
bb
Rei
d-Pr
ovid
ent
A. H
. Rob
ins
Trim
en
Mer
ck S
harp
e an
d D
ohm
e
Smith
KIin
e H
. Sch
ein
Dan
bury
Pha
rmac
al.
Gen
eva
Mer
ck S
harp
e an
d D
ohm
e M
erck
Sha
rpe
and
Doh
me
Gen
eva
Mer
ck S
harp
e an
d D
ohm
e
Lilly
Tab
lets
T
able
ts
Tab
lets
Tab
lets
T
able
ts
Tab
lets
Tab
lets
Su
spen
sion
T
able
ts
Tab
lets
T
able
ts
Tab
lets
In
trav
enou
s T
able
ts
Tab
lets
Tab
lets
Tab
lets
a
2.5
mg,
5 m
g, 1
0 mg
4/50
mg
ia
5/40
mg,
5/8
0 mg
n z * 5 3 25
mg,
50
mg
r! Q 50
mg
50 m
g %
250
mg,
500
mg
2 25
0 m
g 5
ml-'
rn
250
mg,
500
mg
2 25
0 m
g, 5
00 m
g >
250
mg,
500
mg
L?
250
mg,
500
mg
rn 50
0 m
g vi
al
0
2501
0.12
5 m
g t! -1
0
150l
250 m
g, 2
5012
50 m
g 2 rn
XI
n v) 25
010.
125
mg,
500
/0.1
25
mg
Tab
le 3
. C
ontin
ued
Com
poun
d T
rade
Nam
e C
ompa
ny
Dos
age
Form
St
reng
th
Hy d
roch
loro
thia
zide
Hyd
roch
loro
thia
zide
with
Sp
irono
lact
one
Hyd
roch
loro
thia
zide
with
M
ethy
ldop
a H
ydro
chlo
roth
iazi
dc w
ith
Hyd
rala
zine
HC
I
Hyd
roch
loro
thia
zide
with
R
eser
pine
Hyd
roch
loro
thia
zide
with
H
ydra
lazi
ne a
nd R
eser
- pi
ne
Esi
drex
H
ydro
diur
il O
reti
c SK
-Hyd
roch
loro
thia
zide
H
ydro
chlo
roth
iazi
de
Hyd
roch
loro
thia
zide
H
ydro
chlo
roth
iazi
de
Hyd
roch
loro
thia
zide
A
ldac
tazi
de
Hyd
roch
loro
thia
zide
with
Sp
iron
olac
tone
A
ldor
il
Apr
esaz
ide
Apr
esol
ine-
Esi
drex
Se
r- A
pE
s H
ydro
pres
Serp
asil-
Esid
rex
Hyd
roch
loro
thia
zide
with
R
eser
pine
H-H
-R
Hyd
roch
loro
thia
zide
with
H
ydra
lazi
ne H
CI.
Res
er-
pine
R
ezid
e
Cib
a G
eigy
M
erck
Sha
rpe
and
Doh
me
Abb
ott
Smith
Klin
e G
enev
a D
anbu
ry P
harm
acal
. R
oxan
e Pa
rke-
Dav
is
G. D
. Sea
rle
Park
e-D
avis
Mer
ck S
harp
e an
d D
ohm
e
Cib
a G
eigy
Cib
a G
eigy
C
iba
Gei
gy
Mer
ck S
harp
e and
Doh
me
Cib
a G
eigy
G
enev
a
Dan
bury
Pha
rmac
al.
H. S
chei
n D
anbu
ry P
harm
acal
.
Edw
ards
Pha
rmac
al.
Tab
lets
T
able
ts
Tab
lets
T
able
ts
Tab
lets
T
able
ts
Tab
lets
T
able
ts
Tab
lets
Tab
lets
Tab
lets
Cap
sule
s
Tab
lets
T
able
ts
Tab
lets
Tab
lets
T
able
ts
Tab
lets
T
able
ts
Tab
lets
Tab
lets
25 m
g, 5
0 m
g, 1
00 m
g 25
mg,
50
mg,
100
mg
25 m
g, 5
0 m
g 25
mg,
50
mg
25 m
g, 5
0 m
g, 1
00 m
g 50
mg
25 m
g, 5
0 m
g 25
mg,
50
mg
25/2
5 m
g, 5
0/50
mg
25/2
5 m
g
15/2
50 m
g, 2
5/25
0 m
g,
30/5
00 m
g, 5
0/50
0 mg
25/2
5 m
g, 5
0/50
mg,
50
/100
mg
25/2
5 m
g 15
/25 m
g 2Y
0.12
5 m
g, 50
10.1
25 m
g
2Y0.
1 m
g, 5
0/0.
1 m
g 25
10.1
25 m
g, 5
0/0.
125
mg
2Y0.
125
mg,
50/
0.12
5 m
g
W25
I0.1
mg
- 15/2
5/0.
1 mg
Tab
le 3
. C
ontin
ued
Com
poun
d T
rade
Nam
e C
ompa
ny
Dos
age
Form
St
reng
th
Hyd
roch
loro
thia
zide
with
U
nipr
es
Hyd
rala
zine
HC
I and
Re-
se
rpin
e H
ydro
chlo
roth
iazi
de w
ith
Ore
ticyl
D
eser
pidi
ne
Hyd
roch
loro
thia
zide
with
D
yazi
de
Tri
amte
rine
H
ydro
chlo
roth
iazi
de w
ith
Max
zide
T
riam
teri
ne
Hyd
roch
loro
thia
zide
with
Es
imil
Gua
neth
idin
e m
onos
ul-
fate
H
ydro
chlo
roth
iazi
de w
ith
Inde
ride
Pr
opra
nolo
l HC1
H
ydro
chlo
roth
iazi
de w
ith
Mod
uret
ic
Am
iiorid
e H
ydro
chlo
roth
iazi
de w
ith
Tim
olid
e Ti
mol
ol m
alea
te
Rei
d-Pr
ovid
ent
Tab
lets
15
1251
0~1 m
g
Abb
ott
Smith
Klin
e
Tab
lets
35
10.1
25 m
g, 2
510.
125
mg,
Cap
sule
s 25
/50 m
g 50
10.1
25 m
g
Myl
an
Tab
lets
50
175
mg
2511
0 mg
Cib
a G
eigy
T
able
ts
Aye
rst
Tab
lets
25
/40 m
g, 2
5/80
mg
Mer
ck S
harp
e an
d D
ohm
e T
able
ts
5015
mg
Mer
ck S
harp
e an
d D
ohm
e T
able
ts
2511
0 mg
50 m
g H
ydro
flum
ethi
azid
e D
iuca
rdin
A
yers
t Sa
luro
n B
risto
l T
able
ts
50 m
g H
ydro
flum
ethi
azid
e H
. Sch
ein
Tab
lets
50
mg
Hyd
roflu
met
hiaz
ide
with
Sa
lute
nsin
B
risto
l T
able
ts
5010
.125
mg
Res
erpi
ne
Salu
tens
in-D
emi
Bris
tol
Tab
lets
25
10,1
25 m
g H
ydro
-Flu
serp
ine
H. S
chei
n T
able
ts
50/0
-125
mg
Tab
lets
Tab
le 3
. C
onti
nued
Com
poun
d T
rade
Nam
e C
ompa
ny
Dos
age
Form
St
reng
th
Met
hycl
othi
azid
e
Met
hych
loth
iazi
de w
ith
Des
erpi
dine
M
ethy
clot
hiaz
ide
with
C
rypt
enam
ine
Pol y
thia
zide
Po
lyth
iazi
de w
ith P
razo
- si
n H
Cl
Poly
thia
zide
with
Res
er-
pine
Tric
hlor
met
hiaz
ide
Tric
hlor
met
hiaz
ide
Tric
hlor
met
hiaz
ide
with
R
eser
pine
Aqu
aten
sin
End
uron
M
ethy
clot
hiaz
ide
End
uron
yl
Diu
tcns
in
Ren
ese
Min
izid
e
Ren
ese-
R
Naq
ua
Met
ahyd
rin
(M-N
) A
quex
D
iure
se
Kir
krin
al
Roc
hlom
ethi
azid
e Tr
ichl
orm
ethi
azid
e Tr
ichl
orm
ethi
azid
e Tr
ichl
orm
ethi
azid
e
Met
aten
sin
Naq
uiva
l
Wal
lace
A
bbot
t H
. Sch
ein
Abb
ott
Wal
lace
Pfiz
er
Pfiz
er
Pfiz
er
Sche
ring
M
erre
ll L
anne
tt
Am
eric
an U
rolo
gica
l M
oore
-Kir
k R
obin
son
Phar
mec
on.
Cib
a G
eigy
H
. Sch
ein
Mer
rell-
Dow
Sche
ring
Tab
lets
Ta
blet
s Ta
blet
s T
able
ts
Tabl
ets
Tabl
ets
Cap
sule
s
Tabl
ets
Tabl
ets
Tab
lets
Ta
blet
s T
able
ts
Tabl
ets
Tabl
ets
Tab
lets
Ta
blet
s T
able
ts
Tab
lets
Tabl
ets
5 m
g 2-
5 mg,
5 m
g 2.
5 m
gl 5
mg
510.2
5 m
g, 51
0.5 m
g
2.51
2 m
g
1 m
g, 2
mg,
4 m
g 0.
511
mg,
0.5
/2m
g, 0
.515
mg
210.
25 m
g
VI
0
oc
a m ;;1 n E m
r c z z 0
PHARMACOKINETICS OF THE THlAZlDE DIURETICS 509
available; such information has been generated for the most part during the last 5-10 years. The principal reason for this has been the lack of sensitive and specific analytical methods capable of accurately measuring the low concentrations of compounds in biological fluids. A number of early publications, and some more recent, are based on spectrophotometric or flurimetric methods. However, lack of specificity of these procedures has been shown to cause errors in data interpretation,' and they have largely been replaced by more specific and sensitive chromatographic procedures. Even so, these latter methods have been around for some time now and it is surprising that more information has not been generated for this important class of compounds.
Some clinical pharmacokinetic parameters for the thiazide diuretics, as far as they are known, are given in Table 4. The data have been taken from a variety of sources and will be elaborated on in the specific coverage for each drug. Blanks in the table indicate that t information either is not known or was not available to this reviewer.
The data in Table 4 show that, despite their differences in potency, the thiazides have several common pharmacokinetic properties. This is consistent with their similar physical properties. Most of the compounds appear to be reasonably well absorbed from oral doses but some compounds, particularly chlorothiazide, exhibit dose-dependent absorption. In common with many other organic acids, they are generally extensively bound to plasma proteins. They have apparent distribution volumes (calculated from plasma concentra- tions of free and bound drug) equal to or greater than equivalent body weight. Most of the thiazides are actively secreted by the kidneys, although bendroflumethiazide may be an exception. The early literature assigned relatively short elimination half-lives of 1-3 h to many of the thiazides. Development of better analytical methods, and also improved study design and data analysis, have demonstrated more prolonged elimination in some cases. These slower and often extremely variable elimination phases frequently start at about 8-12 h after a single oral dose.
There is no ready explanation for the rather abrupt reduction in drug elimination rate occurring sometime after drug is administered. Changes in the rate of decline in blood levels have been reported for many other drugs. However, in most cases these changes occur within 1-3 h of an intravenous or oral dose. Such changes are often interpreted mechanistically as being due to tissue uptake during the immediate postdose period giving rise to rapid loss of drug from plasma. Once tissue levels equilibrate with plasma levels, the uptake phase ceases and the rate of decline in plasma levels is reduced. The delayed change in elimination rate for the thiazides may also be due to prolonged tissue uptake but it is more likely due to slow release of drug from tissue (for which the drug has relatively high affinity). Whatever the mechanism or mechanisms involved, the effective elimination rates of most
9'
Tab
le 4
. T
hiaz
ide
phar
mac
okin
etic
par
amet
ers
C1,"
Met
abol
ism
**
CL
/' B
Com
poun
d B
ioav
aila
bili
ty*
Pro
tein
v**
tk5
bind
ingt
(%
I (%
) (I
/kg)
(h
) (m
hin
) (m
llm
in)
(%I
Bem
etiz
ide
-
- -
10
-
- B
endr
oflu
met
hiaz
ide
90
95
1-1.
5 9
300
100
Ben
zthi
azid
e lo
w
10
-
10
Chl
orot
hiaz
ide
15-3
0 70
1
1 +2
3$
30
0 30
0 C
yclo
pent
hiaz
ide
-
Cyc
lot h
iazi
de
-
-
-
-
- -
Met
hycl
othi
azid
e -
Pol y
thia
zide
-
-
- -
-
-
-
- -
Hyd
roch
loro
thia
zide
60
-70
40
2-5
9 32
0 32
0 H
ydro
flum
ethi
azid
e 50
-70
40-7
0 5
5-10
45
0 40
0 -
-
-
- -
- -
-
26
-
-
2-5
-
240
Tri
chlo
rmet
hiaz
ide
-
- 70
>90 0 - 0 10
-
* Pe
rcen
tage
of
oral
dos
e ab
sorb
ed.
' Bin
ding
to p
lasm
a pr
otei
ns.
* App
aren
t dis
trib
utio
n vo
lum
e.
* Elim
inat
ion
half
-lif
e.
I' Pl
asm
a or
tot
al b
ody
clea
ranc
e.
** P
erce
ntag
e of
dru
g th
at is
eith
er m
etab
oliz
ed o
r cl
eare
d by
oth
er n
on-r
enal
rou
tes.
est
imat
ed f
rom
uri
nary
rec
over
y of
unc
hang
ed d
rug.
tt
Maj
ority
of
drug
cle
ared
dur
ing
the
shor
t ha
lf-l
ife
phas
e. P
rolo
nged
pha
se o
ccur
s af
ter
12 h
duri
ng w
hich
pla
sma
leve
ls sl
owly
dec
line,
exh
ibiti
ng
saw
-too
th e
ffec
t.
Ren
al c
lear
ance
.
P
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 511
thiazide diuretics have recently been shown to be much slower than originally supposed.
The degree to which the thiazide diuretics are metabolized is extremely variable, ranging from probably extensive metabolism in the case of benzthiazide, bendroflumethiazide, and polythiazide, to only a small extent of metabolism to one metabolite in the case of hydroflumethiazide, to essentially zero metabolism in the case of chlorothiazide and hydrochlor- othiazide.
Although the thiazide diuretics are frequently given together with other drugs, either separately or in combination, there is little information regarding possible drug interactions that may affect bioavailability or pharmacokinetic interactions.
In the following sections literature information for specific compounds is presented in the order analytical, absorption, distribution, metabolism, excretion, and interactions. Chlorothiazide will be discussed first as this is the original compound of this class. Other compounds will be discussed in order of decreasing information on their pharmacokinetics.
CHLOROTHI AZIDE
Analytical During the 1970s a number of colorimetric9 and thin layer
chromatographic"'*' analytical methods were described for chlorothiazide and other diuretic agents. More recently, high pressure liquid chromatogra- phy methods have been described that are specific for chlorothiazide in urine 12.13 and plasma.13
Absorption The absorption of chlorothiazide has been studied extensively in animals
and man. Studies in dogs showed that while chlorothiazide was quantitatively recovered in 48-h urine following 50 mg and 250 mg intravenous (i.v.) doses, urinary recovery from oral (p.0.) doses was lower, and declined with increasing dose size. Following 125 mg, 500mg, and 750mg tablet p.0. doses, mean 48-h urinary recovery in four dogs was 70.4 per cent, 37.2 per cent, and 26.7 per cent, respectively. l 4 The likelihood that reduced absorption at higher doses was due to saturation of the absorption mechanism(s) rather than a formulation effect was supported by a subsequent study in which equally low (means 15.7-22.0 per cent) percentage urinary recoveries were obtained from 500mg doses of 250mg and 500mg tablets, and a p.0. s ~ l u t i o n . ' ~
Saturable absorption of p.0. dosed chlorothiazide has also been demonstrated repeatedly in man. Extending their animal studies to man,
512 PETER G . WELLING
Table 5. Mean chlorothiazide pharmacokinetic parameter values following 125, 250, and 500 mg p.0. solution doses to 12 healthy volunteers*('
Parameter Value 125 mg 250 mg 500 mg
637 921 1314 1 .1 0-9 1 .o 1935 2942 4443
* Maximum concentration of chlorothiazide in plasma. ' Time of maximum concentration. $ Area under the plasma concentration curve from zero to 48 h
Meyer and Straughni6 recovered only 7 per cent of a 500mg p.0. solution dose in 24-h urine of healthy individuals, compared to 33 per cent of a 250 mg dose. Similar dose-dependent absorption was reported by Corrigan and O'Driscoll. '' Urinary recovery of intact chlorothiazide was much less in that study, ranging from 6 per cent of a 1.75 g/70 kg dose to 33 per cent of a 0-21 g/70 kg dose. A poor relationship between dose response and drug excretion rate indicated a saturable response in addition to impaired absorption at high doses. Dose-dependent absorption of chlorothiazide from p.0. solutions has been reported in other studies using doses ranging from 50 mg to 500mg.'8*'9 Although the values vary somewhat between studies, they all follow the same trend.
Reduced absorption of chlorothiazide from high doses is reflected also in circulating drug levels. Mean plasma profiles of chlorothiazide were dose-related but not dose-proportional from 125, 250, and 500mg p.0. solution doses.2" Areas under plasma curves (AUC) increased only 1-5-fold when the dose was increased either from 125 mg to 250 mg or from 250 mg to 500 rng. Some mean pharmacokinetic parameter values obtained in that study are given in Table 5. Times of maximum plasma levels (tm,,) were unaffected by dose. Correlation coefficients between AUC values, and also maximum plasma levels, (C,,,), and urinary recovery of chlorothiazide were 0.65 per cent and 0.75 per cent, respectively. While plasma levels and urinary excretion data both provide a measure of chlorothiazide absorption efficiency, the somewhat lower variability of urine data makes this the method of choice for absorption determination .20321.
Absorption of chlorothiazide from tablets in man follows a similar pattern to that from solution doses. Straughn et ~ 1 . ~ ~ reported poor absorption from 250mg and 500mg tablet doses. Mean urinary recovery ranged from 11 per cent to 16 per cent from the 500 mg doses, and from 16 per cent to 20 per cent from the 250 mg doses. Other studies have confirmed that chlorothiazide
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 513
absorption is only 10-11 per cent from 500mg p.0. tablet doses compared to 17-21 per cent from 2SOmg dose^.^^**^ An in vitro dissolution test for chlorothiazide tablets has been de~cribed. '~
The United States Food and Drug Administration recognized the poor p.0. bioavailability of chlorothiazide by recommending restricted use of the higher dosage strengths and encouraging further studies to examine the bioavailabil- ity and efficacy of lower dosage strengths ranging from S O mg to 250 mg.2h*27
The reason why chlorothiazide exhibits poor absorption qualities compared to some other thiazide diuretics has not been elucidated. It could be related to the relatively high dose of chlorothiazide, but this is unlikely as hydrochlorothiazide absorption is not reduced when it is given in the same dosage range as chlorothiazide.28 The absorption of chlorothiazide has been shown to be interpretable in terms of Michaeles-Menten-type kinetics, but this does not describe the underlying mechanisms involved.29
Although limited absorption of chlorothiazide is generally interpreted in terms of absorption site specificity, and a possible absorption ~ i n d o w , ' ~ . ' ~ , ' ~ it may also be explained in terms of limited aqueous solubility. Chlorothiazide has aqueous solubilities of 0.4 mg ml-l and 1.5 mg ml-l at pH values of 4 and 7, respectively. As dose size increases there is a greater likelihood of reduced dissolution of solid dosage forms, or precipitation from solutions in the acidic fluids of the stomach. Dissolution will occur as drug enters the relatively alkaline small intestine but may not occur rapidly enough from larger doses to permit efficient absorption. This approach finds support in two studies, one of which showed that chlorothiazide absorption is increased when ingested with a large fluid volume,30 while the other showed that chlorothiazide absorption is markedly increased by coadministered propantheline and decreased by met~clopramide.~ ' The rationale in the latter study is that propantheline slows stomach emptying and intestinal motility, thus permitting more time for dissolution and absorption to occur. Metoclopramide, on the other hand, increases stomach emptying rate and may impede absorption by not permitting sufficient drug to dissolve and hence be absorbed in the small intestine. The mean urinary recovery of chlorothiazide from a 500mg p.0. solution dose was 23 per cent, 55 per cent, and 13 per cent when taken alone, with propantheline, and with metoclopramide, respectively. The metoclopra- mide and propantheline effects could also of course be explained in terms of saturable absorption.
The physicochemical explanation for dose-dependent chlorothiazide absorption has been described mathematically by Dressman et ~ 2 1 . ~ ~ In that study a two-tank perfect mixing model was used to simulate G.I. absorption and chlorothiazide behaviour was predicted taking into account drug pK,, solubility, and intrinsic G.I. permeability. The superior absorption qualities of hydrochlorothiazide relative to chlorothiazide were also predicted by the model. Superior bioavailability of chlorothiazide has been reported from a bioadhesive polymer compared to drug powder alone in rats.3' This is again
514 PETER G. WELLING
consistent with the need to retain drug in the proximal region of the G.I. tract for prolonged periods in order to increase absorption.
Distribution As described previously, chlorothiazide plasma levels peak at about 1 h
after p.0. solution doses, indicating fairly rapid absorption. However, peak concentrations are not dose proportional. Typical peak values are ca 600 ng ml-’ and 1300 ng ml-’ following 125 mg and 500 mg doses, respective- ly. Chlorothiazide is 70 per cent bound to plasma proteins and is also actively taken up by red blood cells, giving rise to a blood/plasma concentration ratio of approximately 1.5.34
Elimination Chlorothiazide is not metabolized and is excreted almost entirely as
unchanged drug in the urine. In nephrectomized dogs a considerable proportion of drug is excreted in bile.3’ Most studies report that chlorothiazide is eliminated from plasma with a half-life of 1.5-2.5 h. However, recent studies have shown that, while a considerable proportion of ingested drug is cleared from the body during the initial 12-h period after dosing, at least 50 per cent of drug that is eventually recovered in urine is recovered after the 12-h collection period.3h It is during this period that plasma chlorothiazide concentrations decline quite slowly with a half-life of 15-27 h.30 Plasma concentrations of chlorothiazide in individual subjects are irregular during this period, exhibiting a characteristic saw-tooth effect.”’ The reason for this is not known.
Excellent correlations have been reported between urinary excretion rates and plasma concentrations of chlorothiazide in healthy individuals.”) This is demonstrated in Figure 1 which shows mean plasma concentrations and urinary excretion rates of chlorothiazide in individuals who received single 500 mg tablet doses under non-fasting and fasting conditions. The urinary
TIME (HOURS) TIME (HOURS) TIME (HOURS)
Figure 1. Mean plasma concentrations (0) and urinary excretion rates (0) of chlorothiazide in nine healthy individuals following a single 500 mg dose of chlorothiazide as tablets fasting with 250ml of water (A), fasting with 20ml of water (B), and non-fasting with 250ml of water (C) .
Reproduced by permission from Welling and Barbhaiya”’
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 5 15
excretion and plasma profiles exhibited almost superimposable fast and slow elimination components, the latter extending to at least 48 h postdose.
Detailed studies of chlorothiazide elimination kinetics in monkeys demonstrated that both renal and plasma clearance are dose-dependent, clearances decreasing with increasing dose.37 Renal clearance of chlor- othiazide is reduced by probenecid but active renal secretion is not completely blocked. Very little chlorothiazide appears to be secreted in human breast milk." In a study conducted in 11 nursing mothers, concentrations of chlorothiazide in breast milk during 24 h following ingestion of one 500 mg tablet did not reach a level of 100 ng ml-'. On this basis it was estimated that the infant would receive less than 1 mg of chlorothiazide per day, a clinically insignificant dose.
Interactions Despite the fact that chlorothiazide is frequently administered with other
drugs, and is available in combination products, there have been very few reports examining possible pharmacokinetic interactions between chlor- othiazide and other agents.
Interactions between chlorothiazide and propantheline and metoclopra- mide have already been described in relation to the mechanism of chlorothiazide absorption from the G.I. tract," Inhibition of active renal secretion of chlorothiazide by probenecid has also been described.37 Other clinical studies report interactions between chlorothiazide and lithium.'".'" Chlorothiazide has been shown to increase plasma and red cell concentrations of lithium by ca 25 per cent, and to decrease lithium renal clearance by a similar percentage.39 Appropriate dosage adjustments for lithium in manic depressive patients who might also need thiazide diuretic medication have been de~cr ibed .~" The effect of lithium on chlorothiazide disposition has not been examined.
Although the rat, unlike man, actively excretes chlorothiazide in the bile,'' it also excretes a considerable proportion of drug unchanged in urine." Studies using this animal model have shown that the percentage of dose excreted in urine is approximately doubled by predosing with phen~barbital .~ ' The mechanism of this interaction, which has not been examined in man, was not characterized. However. increased renal blood flow in the presence of phenobarbital was offered as a possible explanation.
HYDROCHLOROTHIAZIDE
Analytical The first published methods to measure hydrochlorothiazide in urine were
based on thin layer chromatography.43 This technique was later adapted to determine drug in plasma and saliva.44 During the mid 1970s a number of gas
516 PETER G. WELLING
chromatography procedures were described.4s47 The use of electron capture detectors was mandatory in order to measure the very low concentrations of circulating drug.
The first high pressure liquid chromatography method to determine hydrochlorothiazide in serum and urine was published in 1976.48 A number of other liquid chromatography assays were described s ~ b s e q u e n t l y . ~ ” ~ ~ The most recent procedures are capable of measuring very small concentrations of hydrochlorothiazide in the circulation as well as the urine, and are highly specific for unchanged drug. ‘3s3754
Absorption Hydrochlorothiazide differs chemically from chlorothiazide only in the
addition of two hydrogen atoms, but the absorption characteristics of the two compounds are remarkably different.
Studies using ‘‘C-hydrochlorothiazide showed that very little drug is absorbed from the stomach, most being absorbed from the duodenum and upper j e j ~ n u m . ’ ~ Urinary recovery of unchanged ’‘C-hydrochlorothiazide accounted for ca 70 per cent of the dose, compared to 90 per cent from an i.v. dose.
The bioavailability of hydrochlorothiazide from commercial formulations has been described in a monograph.‘6 Unlike chlorothiazide, the absorption efficiency of hydrochlorothiazide appears to be independent of dose. In a pilot study in two individuals, urinary recovery of unchanged drug was linearly related to 2.5, 50, and 100mg p.0. doses.57 Plasma levels were proportional to the two lower doses but not to the high dose. In a subsequent study carried out in a larger subject population, urinary recovery of unchanged drug was proportional to 2.5, 50, 100, and 200mg p.0. doses, and
TIME ( H O U R S )
Figure 2 . Mean plasma concentrations of hydrochlorothiazide following single 25 (0). 50 (A), 100mg (B) tablets. and 25 (0), SO (A) . and 100mg (0) suspension doses of hydrochlorothiazide
(n= 12). Reproduced by permission from Patel el a/.”
PHARMACOKINETICS OF THE THlAZlDE DIURETICS 517
TIME ( H O U R S )
Figure 3. Mean cumulative urinary recovery of hydrochlorothiazide following 25 (0). 50 (A) , 100 (B), and 200mg (+) tablet and 25 (0), 50 (A). 100 (0). and 200mg (0) suspension doses of
hydrochlorothiazide (n= 12). Reproduced by permission from Patel ef ~ 1 . ~ '
plasma profiles were proportional to 25, 50, and lOOmg p.0. doses, of both tablets and suspensions of hydrochlorothiazide.2* Mean plasma levels and cumulative urinary excretion of unchanged drug obtained in that study are summarized in Figures 2 and 3. Mean pharmacokinetic parameters are summarized in Table 6. Mean peak plasma levels ranged from ca 130 ng ml-' to 437-490 ng ml-' from the 25 and 100 mg doses, respectively. Times of peak levels were independent of dose and formulation, and areas under plasma curves were dose proportional. Urinary recovery of unchanged drug accounted for 50-60 per cent of the dose, regardless of dose size and formulation. These studies showed that the absorption efficiency of hydrochlorothiazide is independent of dose size over an 8-fold dosage range that extends into the therapeutic dosage range for chlorothiazide. Excellent agreement was obtained between urinary excretion and plasma profile values in this study.
The absorption of hydrochlorothiazide and chlorothiazide thus differs in that, whereas chlorothiazide exhibits a marked saturation or absorption window effect, hydrochlorothiazide absorption efficiency is constant over a wide dosage range. Chlorothiazide absorption efficiency approaches that of hydrochlorothiazide only at the 50 mg dose level."
It is interesting that, although plasma levels and urinary excretion of hydrochlorothiazide are dose proportional, increases in electrolyte excretion are independent of doses in the 25-100 mg range.2x Similar observations to this have been made with chlorothiazide over a 125-500mg range."
Correlations between bioavailability of different hydrochlorothiazide commercial formulations and in vitro dissolution rates are generally poor.5K.s9 This is not too surprising, however, considering the failure of many investigators to demonstrate differences in the absorption of a number of commercial hydrochlorothiazide formulations.h".hl What is perhaps more
518 PETER G . WELLING
surprising is the generally good and constant hydrochlorothiazide absorption from many commercial products despite the identification of hydrochlor- othiazide as a drug with potential bioavailability and bioequivalence problems.62 A discriminative dissolution procedure for hydrochlorothiazide has been proposed based on in vitrolin vivo comparisons of four investigational formulations63 and a standard dissolution criterion for marketed hydrochlorothiazide tablets has been published.64
There have been conflicting reports on the influence of ingested food on hydrochlorothiazide absorption. One study reported increased absorption65 while a second reported decreased absorption66 in the presence of food compared to the fasting state. In the first study mean urinary recovery of hydrochlorothiazide accounted for 63 per cent and 70 per cent of a 75 mg oral dose under fasting and non-fasting conditions, respectively. In the second study plasma levels of hydrochlorothiazide were significantly reduced when the drug was administered after food compared to the fasting state. Urinary recovery was also decreased by food, but differences between treatments were not statistically significant. The different results obtained in the two studies were probably due to the procedures used. Varying the accompanying fluid volume had little effect on hydrochlorothiazide absorption."
Hydrochlorothiazide absorption is markedly impaired in patients who have undergone intestinal shunt surgery for obesity.67 In five patients who received p.0. 75 mg hydrochlorothiazide 1.5-6 years after surgery, urinary recovery of unchanged drug was only 31 per cent of the administered dose.
Absorption of hydrochlorothiazide is generally assumed to obey first order kinetics. However, a recent study has suggested that absorption from ingested tablets may be better described by a zero order process.6x This concept is consistent with a situation in which excess dissolved drug is at the absorption site, or when absorption is saturable. However, there is no evidence that either of these necessarily occurs with hydrochlorothiazide. It would be of interest to know if the observations were specific for the commercial tablets used in the study or are of more general application, particularly in view of good descriptions elsewhere of plasma data based on first order absorption.6'
Absorption of p.0. administered hydrochlorothiazide appears to be reduced by ca 50 per cent in patients with congestive heart failure compared to normal individuals.69 The mechanism of reduced absorption may be related to changes in the intestinal wall or in splanchnic blood flow.
Distribution As shown in Table 6, hydrochlorothiazide plasma concentrations peak at ca
2 h after p.0. doses, achieving values of 120-500 ng ml-' depending on dose size. A number of studies have confirmed that while plasma levels are linearly related to dose size they are not directly related to pharmacokinetic effect. Neither blood pressure lowering'" nor diuresis" increased beyond a certain value with increasing doses of drug.
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 519
Table 6. Mean hydrochlorothiazide pharmacokinetic parameter values following single 25, 50, 100, and 200mg suspension doses to 12 healthy
Parameter Value 25mg 50mg 100mg 200mg
Tablet * Cmax (ng m1-l) 127 280 437 -
48-h Urinary recovery (%) 63 55 50 54
2.4 2.1 2.3 - ?$C6!?% (ng h m l - l ) 978 1968 3554 -
Suspension 134 270 490 -
- Cmax (ng m1-l) Tmax 2.4 1.8 1.8
48-h Urinary recovery (%) 60 54 59 57 AUC"36 (ng h ml-') 1038 1910 3993 -
* Not determined.
The profile of hydrochlorothiazide in plasma differs markedly from that of chlorothiazide during the post-absorptive phase. Chlorothiazide exhibits an initial rapid fall in plasma levels until ca 12 h and then declines irregularly. Hydrochlorothiazide concentrations also fall rapidly until 12 h, but then decline at a slower but consistent rate with a terminal half-life of 8-10 h.'3.hh The mechanism underlying the biphasic elimination of hydrochlorothiazide from plasma is unclear, but as suggested previously for chlorothiazide, is probably related to slow release of drug from tissues. Hydrochlorothiazide accumulates in red cells, but equilibrium of drug between plasma water and red cells is reached within 4 h of a p.0. dose.7'
As with chlorothiazide, excellent agreement has been demonstrated between urinary excretion rates and plasma profiles of hydrochlorothiazide. The superimposability of these parameters in three individuals following a single 50mg p.0. dose of drug is demonstrated in Figure 4. As commented earlier in this review, excellent agreement has also been demonstrated between plasma profiles and cumulative urinary excretion of hydrochloro- thiazide at different dose levels. 28
Hydrochlorothiazide crosses the human placenta efficiently and achieves levels in umbilical cord plasma similar to those in maternal plasma.72 The concentration of hydrochlorothiazide in amniotic fluid on the other hand is higher than in maternal and umbilical cord plasma. This contrasts with chlorthalidine which achieves levels in amniotic fluid only 3-12 per cent of those in p l a ~ m a . ~ ' If the differential binding of chlorthalidine and hydrochlorothiazide to erythrocytes is taken into account, the two drugs appear to diffuse through fetal membranes to a similar degree. While
520 PETER G . WELLING
TIME (HOURS) TIME (UOURS) TIME (HOURS)
Figure 4. Plasma concentrations (0) and urinary excretion rates (0) of hydrochlorothiazide in three healthy subjects following a single 50mg p.0. dose. Reproduced by permission from
Barbhaiya et al.'?
hydrochlorothiazide ingested by the mother is capable of reaching the fetal circulation at concentrations similar to those in maternal circulation, it appears not to reach the nursing infant by means of ingested breast milk. Hydrochlorothiazide, in common with chlorothiazide, achieves very low levels in breast milk relative to maternal blood after therapeutic doses, and does not produce measurable drug levels in the nursing infant.74
Elimination Hydrochlorothiazide is not metabolized in man and is excreted almost
entirely as unchanged drug in urine. Renal clearance is ca 300ml min-', indicating combined glomerular filtration and proximal renal tubular secretion.hh In patients with impaired renal function, the rate of hydrochloro- thiazide elimination is reduced. In a typical study, the elimination half-life of hydrochlorothiazide was increased from a mean value of 6.4h in normal individuals to 11.5 h in patients with a mean creatinine clearance of 60ml min-', and to 21 h in patients with a mean creatinine clearance of 19ml min-I.'' In functionally anephric patients, the elimination half-life is ca 34 h.
Although the renal elimination of hydrochlorothiazide is prolonged 5-fold in severe renal impairment, this is a relatively small increase considering that the kidneys represent the only elimination pathway in normal individuals. It appears that a non-renal excretion mechanism, as yet unidentified, plays an increasingly important role in hydrochlorothiazide elimination as renal function deteriorates.
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 521
Interactions A considerable number of reports have been published in which the
absorption or disposition of either hydrochlorothiazide or other agents is affected due to interactions. Many of these are clinically relevant due to frequent administration of hydrochlorothiazide together with other drugs or in combination formulations.
Hydrochlorothiazide shares with chlorothiazide the property that its absorption efficiency is increased by agents that reduce G.I. m ~ t i l i t y . ~ ' Propantheline delayed peak hydrochlorothiazide levels in plasma from a mean control value of 2.4 h to 4.8 h in healthy volunteers and increased 48-h urinary recovery from 66 per cent to 89 per cent of a 75 mg p.0. dose.76 The centrally acting a-adrenergic agonist guanabenz also increased hydrochloro- thiazide absorption, resulting in somewhat higher C,,, (mean 168 vs 146 ng ml-'), and significantly higher AUC (mean 1035 vs 887 ng h ml-', p < 0.05) following single doses of 16 mg guanabenz and 25 mg hydrochlorothiazide compared to 25 mg hydrochlorothiazide administered alone.77 Coprecipita- tion with polyvinylpyrrolidone 10 OOO increased the absorption of hydrochloro- thiazide to a small but significant extent compared to hydrochlorothiazide administered alone.78 While the mechanism of this effect is clearly related to dissolution, the molecular nature of the interaction is uncertain because a mechanical mixture of the two compounds had a similar effect to the coprecipitate.
Non-absorbable and ionic exchange resins have different effects o n the absorption of hydrochlorothiazide, and also a number of other drugs. In the rat, coadministered cholestyramine reduced hydrochlorothiazide availability by 42 per cent, while colestipol had no significant effect.79 Similarly, in man cholestyramine reduced mean peak concentrations of hydrochlorothiazide in
= 300- E
E. 250- 0
. c1)
W
N 2 200-
Q 100-
I- 0
V
TIME (HOURS)
Figure 5 . Mean plasma concentrations of hydrochlorothiazide following a p.0. dose with water, colestipol, or cholestyramine. Bars indicatc S.E.M. Reproduced by permission from
Hunninghake et al.""'
522 PETER G . WELLING
plasma by 69 per cent, compared to 14 per cent for colestipol, and reduced 24-h urinary recovery of hydrochlorothiazide by 83 per cent compared to 43 per cent for colestipol.80 Mean plasma hydrochlorothiazide concentrations when administered alone, and in the presence of these two agents, are shown in Figure 5.
Hydrochlorothiazide is frequently administered together or in fixed combination with P-adrenergic receptor blocking agents. There has naturally been considerable interest in the degree to which the compounds may interact to influence one or the other drug. Results to date have been surprisingly benign. No significant pharmacokinetic interactions have been noted between hydrochlorothiazide and propranolol,81 metoprolol,82 sota101,~~*'~ or acebutol01~~ when these agents are administered together, separately, or in fixed combination. Similar lack of significant interactions have been noted between hydrochlorothiazide and spironolactone,86~s7 indomethacin,88 allo- purinol and oxipurinol,x' and phenytoin.'"
The nature of possible interaction between hydrochlorothiazide and the potassium-sparing diuretic triamterine has been somewhat controversial. Early studies on the bioavailability of the components of a fixed drug combination of hydrochlorothiazide and triamterine demonstrated consider- able differences in the absorption of both compounds from capsules compared to compressed tablets,9' poor bioavailability of both compounds from combination tablets and capsules,y2 and marked reduction of hydrochlorothiazide availability, but little loss of triamterine bioavailability from a combination formulation compared to when the drugs were administered alone.'3 More recent studies indicate that apparent interactions between the two compounds in combination products may have been due to a formulation effect rather than any direct drug-drug interaction. With appropriate fixed combination formulations, similar absorption of both drugs can be attained to that when drugs are administered separately.9496 Caution is recommended in the clinical use of different commercial fixed combinations of hydrochlorothiazide and triamterine because of differences in strength in the bioavailability of the two
No differences in blood levels of propranolol were noted between a combination product containing propranolol, triamterine, hydrochloro- thiazide, and when propranolol was administered alone."
BENDROFLUMETHIAZIDE
Analytical The average daily dose of bendroflumethiazide is 5mg. The drug has an
apparent distribution volume approximately equivalent to body weight. Combination of these factors results in low circulating drug concentrations, and inevitable analytical problems. Initial colorimetric proceduresyy.'"" to
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 523
Table 7. Mean bendroflumethiazide pharrnacokinetic parameter values following single 1.25, 2.5, 5.0, and 10.0 mg p.0. tablet doses to healthy individual^^"^."'^."'^
Parameter Value 1.25 mg 2.5 mg 5.0 mg 10.0 mg
Cmax (ng rn1-I) Tmax (h) AUC (ng h ml-') 48-h Urinary recovery as unchanged drug (%)
9.2 16 33.7 86 2.5 2.0 2.0 2.0 61 113 33 1 473
* Not determined.
determine bendroflumethiazide in biologica! fluids have been replaced by more sensitive gas chromatography,"' fluorodensitometric,Io2 and, more recently, liquid chromatographic'"3 methods.
Absorption When 9 mg 35S-bendroflumethiazide was administered p.0. to healthy
subjects, the label was recovered almost quantitatively in 24-h urine indicating complete absorption of label. Io3 As bendroflumethiazide, unlike chlorothiazide and hydrochlorothiazide, is extensively metabolized in man,"" the fraction of dose that is absorbed unchanged in not known. Unchanged drug is absorbed rapidly, maximum drug concentrations occurring in plasma within 1.5-2.5 h of dosing. Both the plasma levels and cumulative urinary excretion of bendroflumethiazide are proportional to single p.0. doses of 1.25, 2.5,Io4 and 10mg.'" Neither the rate nor extent of bendroflumethiazide absorption appear to be affected by food. Io5
Distribution Some pharmacokinetic parameters associated with circulating levels of
bendroflumethiazide after p.0. doses are summarized in Table 7. Peak plasma concentrations ranging from 9 to 90 ng ml-l from 1.25 to 10 mg doses occur at 2 h postdose. Plasma bendroflumethiazide concentrations were initially reported to decline monoexponentially with a half-life of ca 3 h. "" However, more recent reports have identified a slower, terminal elimination phase which has a half-life of ca 9 h.lo4 The slower terminal phase starts at about 8-10 h postdose so that, in this respect, bendroflumethiazide closely resembles hydrochlorothiazide. Bendroflumethiazide pharmacokinetic para- meters were not altered after repeated daily 2.5 mg doses.1o4
Bendroflumethiazide is approximately 95 per cent bound to human albumin.'"6 Its body distribution volume has been estimated at 1-1.5 1 kg-'."".'02 However, this value is based on circulating levels of total (both
524 PETER G. WELLING
free and bound) drug so that the actual distribution volume based on free drug is far greater.
Comparison of plasma and blister fluid bendroflumethiazide concentra- tions showed the blister fluid levels often equalled or exceeded those in plasma."' Drug concentrations in blister fluid declined at a similar rate to those in plasma, and could be associated pharmacokinetically with a peripheral compartment.
Elimination Unlike chlorothiazide and hydrochlorothiazide, bendroflumethiazide is
extensively metabolized, only 30 per cent of administered drug appearing unchanged in urine."' The fate of the remaining 70 per cent appears not to have been examined. Renal clearance of bendroflumethiazide has been variously estimated at between 30L04 and 10510',"'7 ml min- , while non-renal clearance is 270-400 ml min-I. 1013107 Elimination kinetics are linear over the dosage range 23-10 mg. Io7
No accumulation of bendroflumethiazide was observed during repeated 2.5 or 5.0mg daily doses to hypertensive patients.lo8 This indicates that the prolonged 'beta' elimination phase of ca 9 h plays only a minor role in repeated dose kinetics for this compound. While plasma concentrations in this study were proportional to dose, renal clearance of unchanged drug after the 5mg dose was only one-half that after the 2.5mg dose. It is not certain whether accumulating metabolites could have interfered with renal excretion of unchanged drug in the multiple dose regimen.
Interactions The bioavailability and pharmacokinetics of bendroflumethiazide have
been shown not to be significantly affected by propranolol following single or repeated doses, either as a fixed or free-combination."'".'"' They were similarly unaffected in a fixed combination with propranolol and
TIME (HOURS) TIME (HOURS) TIME (HOURS)
Figure 6. Mean plasma concentrations of bendroflumethiazide. propranolol, and hydralazine in seven healthy volunteers after single p.0. doses of a fixed combination: 2.5 mg bendro- flumethiazide, 60 mg propranolol. 25 mg hydralazine (0) and equal doses of each drug given alone (+). Bars indicate S.E.M. Reproduced by permission from Schafer-Korting and
Mutschler""
PHARMACOKINETICS OF THE THlAZlDE DIURETICS 525
hydralazine.”’ Hydralazine concentrations increased by approximately 60 per cent from the combination product compared to when the drug was administered alone. However, due to data variability this increase was not statistically significant (p > 0.05). Mean plasma concentrations obtained in that study are shown in Figure 6.
HYDROFLUMETHIAZIDE
Analytical The dosage range of hydroflumethiazide is 25-200 mg daily. While this
dosage is far greater than that of bendroflumethiazide, circulating drug levels are generally less than 1 pg ml- I .
Methods have been described to quantitate hydroflumethiazide in biological fluids based on extraction and fluorescence measurement, ’ ’ and on fluorometric thin layer chromatograhpy. ’ I 3 A liquid chromatographic method has been described to measure hydroflumethiazide in formulations. ‘ I 4 However, to the writer’s knowledge this type of procedure has not been described for biological fluids, and current pharmacokinetic studies are based on the thin layer separation.
Absorption Hydroflumethiazide is efficiently and quite rapidly absorbed after p.0.
doses, achieving maximum concentrations in the circulation by 2-2-5 h. ’ I 5
Based on relative quantities of unchanged drug voided in urine, hydrof- lumethiazide was estimated to be 73 per cent bioavailable after single 50 mg p.0. doses and 53 per cent bioavailable after single 125-200 mg p.0. doses. ’ I6 Although the difference between these values was not significantly different (p > 0.05), it none the less raises the question as to whether hydroflumethiazide might exhibit similar saturable absorption characteristics to chlorothiazide.
Whereas most pharmacokinetic studies have assumed first order absorption of hydroflumethiazide re-evaluation of published data’ Is has suggested that, as was previously suggested for hydrochlorothiazide,h8 hydroflumethiazide absorption may be more accurately described by zero order kinetics. ’ ” This conclusion is based on comparison of correlation coefficients, standard deviations of parameter estimates, and visual examination of fits of data to zero order and first order absorption models.
Distribution Hydroflumethiazide is approximately 40-70 per cent bound to plasma
proteins and the drug has an apparent distribution volume in the body of ca 4-51 kg-’.”6,’1s.’” It accumulates slowly into red cells to achieve a red ce1l:plasma concentration ratio of 1.7. ‘ I 8
526 PETER G. WELLING
Following single i.v. doses of 46mg and 44mg to two individuals, peak hydroflumethiazide concentrations of 800-900 ng ml-' were obtained im- mediately postinfusion. Plasma concentrations then declined in a triphasic manner with associated half-lives of 0-26,0.84, and 5.2 h.'16 Following single p.0. doses of 100 mg, a mean peak hydroflumethiazide plasma concentration of 390ngml-' was obtained at 2-5 h.'I5 Various studies have examined hydroflumethiazide elimination kinetics following oral p.0. doses. Typical reported elimination half-lives range from 2 h'" to 8.7 h.'18
Elimination Hydroflumethiazide is eliminated from the body predominantly as
unchanged drug, accounting for 90 per cent of absorbed compound, but is also cleared to a small extent by metabolism. The major metabolite 2,4-disulfamyl-5-trifluoromethylaniline (DTA) is cleared via the urine. This metabolite is cleared from the body more slowly than the parent drug and has a plasma elimination half-life of ca 18h."' The longer half-life of DTA may be due, at least in part, to its accumulation in red cells.'I8 Renal and plasma clearance of hydroflumethiazide are 450 and 520ml min-', respectively. ' 1 6 * ' l 9
Only 0.05 per cent of a single p.0, dose of hydroflumethiazide was recovered in 6 h bile of five healthy individuals with a T-drain in the common bile duct. This confirms the minor role of biliary excretion for this drug.'*"
Two studies have examined the pharmacokinetics of hydroflumethiazide in patients with cardiac failure. In a study comprising five healthy subjects and nine patients with moderate cardiac failure, a shorter mean elimination half-life of 9.6h was observed in patients compared to 16-6h in healthy subjects.'*' This observation was rationalized in terms of reduced overall distribution volume for hydroflumethiazide in patients overcompensating for decreased renal clearance. In a subsequent study in congestive heart failure patients, the elimination half-life of hydroflumethiazide ranged from 6-5 to 27.9 h.'I9 Poor correlations between drug clearance and creatinine clearance were interpreted in terms of either altered drug distribution or an increased contribution by non-renal elimination routes. In this study the mean elimination half-life of hydroflumethiazide was shorter (9.2 h) in patients who received 75mg doses compared to patients who received 150mg doses (14.1 h). Similar dose-dependent elimination has been suggested in normal healthy individuals.
BEMETIZIDE
Analytical In view of the very small fraction of unchanged bemetizide that is recovered
or is at least measurable in urine, sensitive analytical procedures are required
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 527
to measure both circulating levels and urinary excretion. Two methods have been described. The first involves extraction and thin layer chromatographic separation. lZ2 The second involves reverse phase liquid chromatography. 123
The second method has been extensively characterized and is probably the method of choice for this compound.
Absorption The absolute absorption efficiency of bemetizide from p.0. doses has not
been determined. In a preliminary study a 25 mg p.0. dose was administered to six healthy volunteers. A mean peak drug concentration of 75ngml-' occurred at 4 h postdose, concentrations then declined to 35 ngml-' at 12 h. Only 3 per cent of administered drug was recovered unchanged in 0-12 h urine. The possibility of dose-dependent bemetizide absorption was suggested in a study in which healthy male volunteers received single 1, 5, 10, 20, and 50mg p.0. doses of drug. Analysis of plasma data from the 5, 10,20, and 50mg doses showed that the time of maximum drug concentration in plasma (means 2.9-3.5 h) and apparent elimination half-life (means 3.7-4.4 h)
2 100
V EL 0
0 10 20 30 40 50 1600 i
- 0 16 20 30 40 50 BEMETlZlDE DOSE (mg)
Figure 7 . Relationships betweem mean C,,,,, AUC, and urinary recovery, and dose of bemetizide in seven healthy male volunteers. Bars indicate S .D . Reproduced by permission from
Piper er a / . 'Iz
528 PETER G . WELLING
were dose-independent. Maximum plasma levels and areas under plasma curves were also dose-independent between the 5 mg and 20 mg doses, but increased by only 40-50 per cent between the 20mg and 50mg doses. Although only a small percentage of dose was recovered unchanged in urine, this parameter exhibited similar characteristics to plasma levels. Rela- tionships between plasma and urinary excretion parameters, and dose of bemetizide, are summarized in Figure 7.
Distribution In common with other thiazide diuretics, bemetizide is fairly extensively
distributed such that plasma levels are in the ng ml-' range. Typical plasma concentrations are shown in Figure 7. The rate at which bemetizide leaves plasma, again in common with other thiazide diuretics, is variable and different values have been reported. '22-124 Probably the most accurate measurement was obtained in a recent interaction study with triamterine. 124
In that study two different bemetizide formulations gave rise to mean elimination half-life values of 11.2 h and 8.4 h.
Elimination The mechanism(s) by which bemetizide is cleared from the body is not well
characterized. Only 2-4 per cent of single p.0. doses have been recovered in urine, suggesting that the molecule is either poorly absorbed, extensively metabolized or both. 122,'24 However, bemetizide is unstable in urine, and the proportion of dosed drug measured in urine does not necessarily represent total urinary excretion of unchanged drug. More work is needed to characterize the bioavailability, distribution, and eventual fate of orally administered bemetizide.
Interactions One study has examined interaction between bemetizide and triamterine in
a fixed combination tablet.'24 The mean peak plasma concentration of bemetizide was reduced from 88 ng ml-I when 25 mg bemetizide was given alone, to 68ngml-' in combination with 50mg triamterine. On the other hand, peak plasma levels of triamterine increased from 16 ngml-' when given alone to 45ngml-' in combination. Areas under plasma curves and also urinary excretion of unchanged drugs were consistent with plasma values despite the fact that mean urinary recovery of total bemetizide and triamterine represented less than 4 per cent and 2 per cent, respectively, of administered doses.
While these results might suggest an interaction between bemetizide and triamterine, the study design cannot support this conclusion unequivocally because the two drugs were not administered together in free combination to test for formulation effects on their relative bioavailability.
PHARMACOKINETICS OF THE THIAZIDE DIURETICS
TRICHLORMETHI AZIDE
529
Analytical Trichlormethiazide is administered at doses of 1-4 mg, giving rise to low
circulating concentrations of drug. Liquid chromatography analytical procedures have been described for trichlormethiazide in plasma and urine. 125 The methods are reported to be specific for unchanged drug but no sensitivity or reproducibility details are given. An alternative method has been described for trichlormethiazide in urine only. 126 This method has a lower sensitivity limit of 2 pg ml-' and has a coefficient of variation of less than 2 per cent at a concentration of 40 yg ml-I.
Absorption Absolute bioavailability data for trichlormethiazide are not available.
Following a 4 mg tablet dose 62 per cent of administered drug was recovered unchanged in urine.lZ6 The fate of the other 38 per cent is unknown, although no metabolites were reported to be present in urine.'25 Peak plasma concentrations occur at ca 2 h postdose. Absorption of trichlormethiazide from p.0. tablets is accelerated by coadministered antacid, presumably by raising gastric pH and thereby increasing the solubility of this poorly water soluble weak acid, but overall absorption efficacy was not affected. Following the antacid treatment, 2.41 mg of a 4 mg dose of trichlormethiazide was recovered in 24-h urine, compared to 2-46mg in the absence of antacid.
Distribution Following a single 4 mg tablet p.0. dose to seven healthy individuals, peak
plasma concentrations of 29-67 ngml-l were obtained at 1.3-2.5 h. Plasma levels declined with an apparent half-life of 1-2-4.1 h.
Elimination Trichlormethiazide is cleared from the body mainly in unchanged form in
the urine. Renal clearance is 240 ml min-l, indicating both renal filtration and tubular secretion.
In patients with compromised renal function elimination of trichlor- methiazide is impaired, the elimination half-life varying from 5 h in a patient with creatinine clearance of 64 ml min-' to 10.4 h in a patient with creatinine clearance of 5 ml min-'.'*' Surprisingly, the quantity of unchanged drug voided in urine during 48 h postdose was not significantly affected by renal impairment, precluding any additional contribution of nonrenal elimination pathways.
530 PETER G . WELLING
POLYTHIAZIDE
Analytical The first sensitive and specific analytical procedure for polythiazide,
another potent low dose thiazide diuretic, was described by Hobbs and Twomey.128 This method involved extraction and hydrolysis to form tnfluoroethylthioacetaldehyde, which is then quantitated by gas chromato- graphy with electron capture detection. The method is sensitive down to a polythiazide concentration of the 0.2 ng ml-l in plasma, with acceptable reproducibility. A liquid chromatography procedure for polythiazide, simultaneously with prazosin, was described subsequently. 12' This method, which incorporates extraction, microcolumn purification, separation on a p Bondapak CN column, and spectrophotometric detection, is sensitive down to polythiazide concentrations of 0.5 ng ml-' in plasma. It thus loses some of the sensitivity associated with the gas chromatography method, but gains in avoiding a derivatization step and also by incorporating an internal standard. As the metabolism of polythiazide has not been examined, the specificity of the above assays for polythiazide in the presence of possible metabolites is unknown.
Pharmacokinetics Information regarding the metabolism and pharmacokinetics of
polythiazide, in experimental animals or man, is meagre. Following 0.1 mg kg-' p.0. or i.v. doses to dogs, 80-85 per cent of the dose
was recovered in 5-day urine, and 15-20 per cent in faeces. The bulk of the drug was eliminated during the first 24 h postdose.'") Following high (100 mg kg-I) i.v. doses, 35-45 per cent of administered drug was recovered in 5-day urine and 20-30 per cent in faeces. Polythiazide is excreted partially as unchanged drug and ca 30 per cent as a degradation product 3- (methylsulfamyl)-4-amino-6-chlorobenzenesulfonamide. Following single doses of 1 mg polythiazide as commercial tablets to healthy volunteers after overnight fast, mean plasma concentrations of unchanged drug yielded ;I peak value of 3-2 ng ml-l at 5 h postdose. "() The concentration then declined monoexponentially with a half-life of 26 h. The long plasma half-life is consistent with prolonged duration of action of polythiazide. 1 3 1 , 1 3 2 Only 14 per cent of the administered dose was recovered as intact drug at 24 h, and 20 per cent at 48 h. From the plasma half-life of 26 h, total urinary recovery may account for 25 per cent of the dose. This figure is similar to the recovery in dogs following single i.v. doses. If one ignores the difference in dose size and possible species differences, one could conclude that polythiazide is efficiently absorbed in man and approximately 75 per cent of administered drug is cleared by extrarenal routes. However, more experimentation is needed to determine the relative contributions of possibly low bioavailability on the one hand, and extrarenal clearance on the other, to low urinary recovery of orally administered polythiazide in man.
PHARMACOKINETICS OF THE THIAZIDE DIURETICS
BENZTHIAZIDE
531
Analytical The usual daily dose of benzthiazide is 25-100mg. The drug is practically
insoluble in water and thus has potential for low bioavailability from p.0. doses. The first specific assay for benzthiazide in plasma, urine, and faeces was recently described by Meyer et a1.'33
Pharmacokinetics Use of the above analytical methodology to examine benzthiazide
absorption from 50mg p.0. tablet and solution doses to healthy male individuals showed that absorption was very p 0 0 r . l ~ ~ Although the assay for plasma was sensitive down to drug concentrations of 10 ng ml-', no drug was detected after p.0. tablet doses in two individuals, and concentrations of only 4 ,8 , and 6ngml-' were detected at 2 ,3 , and 4 h postdose in another. Urinary recovery of unchanged drug was less than 1 per cent of the dose while faecal recovery was ca 80 per cent.
While other explanations, including a large distribution volume, biliary excretion, and extensive metabolism could possibly contribute to the low plasma levels and to negligible urinary recovery of benzthiazide, low bioavailability is the most probable cause. This is supported by the poor dissolution characteristics of benzthiazide tablets in a variety of standard dissolution tests.134
CYCLOPENTHIAZIDE
Cyclopenthiazide is administered in very small, often submilligram doses. Measuring concentrations of this agent in biological fluids thus offers a considerable challenge to the analytical chemist, one that apparently has not yet been accepted, as demonstrated by the absence of pharmacokinetic information for this agent.
The value of this agent in combination with P-adrenergic blocking agents appears to be somewhat controversial. One study reports a significant reduction in systolic and diastolic blood pressures when a once-daily dose of oxprenolol and cyclopenthiazide is substituted for conventional therapy with a single fLblocking agent.'35 However, improvement in therapeutic response may have been due, at least in part, to improved patient compliance with the once daily dosage of the long acting combination. A subsequent study could not demonstrate a clinical advantage of oxprenololkyclopenthiazide com- bination compared to oxprenolol given a10ne.l~' The author of that communication recommended additionally that twice daily dosage of oxprenolol may be necessary for adequate 24-h P-adrenergic receptor blockade.
532 PETER G. WELLING
A number of studies have examined the renal distribution of cyclo- penthiazide, and factors affecting this, and have presented some interesting comparisons between cyclopenthiazide and other agents actively secreted into renal tubules. For example, cyclopenthiazide has been shown to accumulate in rat renal cortical slices, due to active tubular transport, to a greater extent than p-aminohippurate. 13’ Unlike p-aminohippurate, cyclopenthiazide accu- mulation is not affected by inhibition of energy supply. On the other hand, renal excretion of cyclopenthiazide is decreased by the renal transport inhibitors 2,4-dinitrophenol, iodoacetate, and probenecid. 138 After repeated doses to adult rats, cyclopenthiazide, together with phenobarbital and probenecid, may increase renal excretion of p-aminohippurate. 139
REFERENCES
I . F. C. Novello and J . M. Sprague. 1. Am. Chem. SOC., 79, 2028 (1957). 2. F. C. Novello, S. C. Bell, E. L. A. Abrams, C. Ziegler and J . M. Sprague, J . Org. Chem.,
25, 970 ( 1960). 3. G. H. Mudge, in The Pharmacological Basis of Therapeufics, A. G . Gilman, L. S.
Goodman and A. Gilman (Eds), 6th edn, 1980, p. 899. 4. E. D. Fries and I . M. Wilson, Med Ann. D.C. , 26, 468 (1957). 5. E. D. Fries, A. Wanko, I . M. Wilson and A. E . Parrish, J . Am. Med. Assoc.. 166, 137
(1958). 6. A. Lant, Drugs, 29, 57 (1985). 7. E. D . Fries, Am. Heart J . , 106, 185 (1983). 8. D. E . Resetarits and T. R. Bates, J . Pharm. Sci., 68, 126 (1979). 9. D. Suria, Clin. Biochern., 11. 222 (1978).
10. S . J . Stohs and G . A. Scratchley, 1. Chrornafogr., 114, 329 (1975). 11. J. E . Wallace, H. E. Hamilton, H. Skrdland, L. L. Burkett and H. Schwertner, J .
12. P. A. Tisdall, T. P. Moyer and J . P. Anhalt, Clin. Chem., 26. 702 (1980). 13. R. H. Barbhaiya, T. A. Phillips and P. G . Welling, J . Pharm. Sci., 70, 291 (1981). 14. D. E. Resetarits and T. R. Bates. 1. Pharmacokinet. Biopharm., 7, 463 (1979). 15. W. F. Ebling, A. F. Murro, F. J . Voelker, D. E. Resetarits and T. R. Bates, J . Pharm. Sci..
16. M. C. Meyer and A. B . Straughn, Curr. Ther. Res., 22, 573 (1977). 17. 0. J . Corrigan and K. M. O’Driscoll, 1. Pharm. Pharmacol., 32, 547 (1980). 18. V. P. Shah, J . Lee, J . P. Hunt. V. K . Prasad, B. E. Cabana and T. Foster, Curr. Ther. Res. ,
19. M. A. Osman, R. B. Patel, D. S. Irwin, W. A. Craig and P. G. Welling, Biopharm. Drug
20. P. G . Welling, R . H. Barbhaiya, R. B. Patel, T. S. Foster, V. P. Shah. J . P. Hunt and V. K.
21. V. P. Shah, J. P. Hunt, V. K. Prasad and B. E. Cabana, J . Pharm. Sci., 70. 833 (1981). 22. A. B. Straughn, A. P. Melikian and M. C. Meyer, J . Pharm. Sci., 68. 1099 (1979). 23. P. G . Welling, D. M. Walter, R. B . Patel, R . H. Barbhaiya. W. A. Porter, G. L. Davidson.
T. S. Foster, V. P. Shah, J . P. Hunt and V. K. Prasad, Curr. Ther. Res., 29, 815 (1981). 24. V. P. Shah, J . Lee, J . P. Hunt, V. K . Prasad, B. E . Cabana and T. S . Foster, Curr. Ther.
Res. , 29, 802 (1981). 25. V. P. Shah, P. Knight, V . K. Prasad and B. E. Cabana, J . Pharm. Sci., 71, 822 (1982). 26. Food and Drug Administration, FDA Drug Bull., 11 13 (1981). 27. P. G . Welling and V. P. Shah, Am. J . Hosp. Pharm., 41, 450 (1984). 28. R. B. Patel. U . R . Patel, M. C. Rogge, V. P. Shah, V. K. Prasad, A. Selen and P. G .
Chromafogr., 138, 111 (1977).
70, 224 (1981).
29, 823 (1981).
Dispos., 3, 89 (1982).
Prasad, Curr. Ther. Res., 31, 379 (1982).
Welling, J . Pharm. Sci., 73, 359 (1984).
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 533
29. J . H . Wood and K. M. Thakker. Eur. J. Clin. Pharmacol., 23, 183 (1982). 30. P. G. Welling and R . H . Barbhaiya, J. fharm. Sci., 71, 32 (1982). 31. M. A. Osman and P. G. Welling, Curr. Ther. Res., 34, 404 (1983). 32. J. B. Dressman, D . Fleisher and G . L. Amidon, J . fharm. Sci., 73, 1274 (1984). 33. M. A . Longer, H . S. Ch'ng and J. R. Robinson, J. Pharm. Sci., 74, 406 (1985). 34. V. P. Shah, M. A . Walker, J . P. Hunt, D . Schuirmann, V. K. Prasad and B. E. Cabana,
35. J. E. Baer, H . L. Leidy, A . V. Brooks and K. H . Beyer, J. Pharmacol. Exp. Ther., 125,295
36. V. P. Shah, V. K. Prasad, B. E. Cabana and P. Sojka, Curr. Ther. Res., 24, 366 (1978). 37. J. H . Gustafson and L. Z. Benet, J. Pharmacokinet. Biopharm., 9, 461 (1981). 38. M. W. Werthmann Jr. and S. V. Krees, J. Pediatrics, 81, 781 (1972). 39. R. I . Poust, A . G . Mallinger, J. Mallinger, J . M. Himmelhoch, J . F. Neil and I. Hanin,
40. J. M. Himmelhoch, R. I. Poust, A . G. Mallinger, 1. Hanin and J. F. Neil, Clin. Pharmacol.
41. L. G . Hart and L. S. Schanker, A m J. fhysiol., 211, 643 (1966). 42. E. E. Ohnhaus, Experientia, 28, 821 (1972). 43. M. J. Stumph and M. W. Noall, J. Anal. Toxicol., 8, 170 (1964). 44. M. Schafor, H . E. Geissler and E. Mutschler, J. Chromarogr., 143, 615 (1977). 45. B. Lindstrom, M. Molander and M. Groschinsky, J . Chromatogr., 114, 459 1975. 46. W. J . A. Vandenheuvel, V. F. Gruber, R. W. Walker and F. J . Wolf, J. fharm. Sci., 64,
47. E. Redalieu, V. V. Tipnis and W. E. Wagner, Jr. J. fharm. Sci., 67, 726 (1978). 48. M. J . Cooper, A . R. Shinalko, M. W. Anders and B. L. Mirkin, Anal. Chem., 48, 1110
49. A . S. Christophersen. K. Rasmussen and B. Salvesen, J. Chromatogr., 132, 91 (1977). 50. W. T. Robinson and L. Cosyns, Clin. Biochem.. 11, 172 (1978). 51. S. J . Soldrin, E. Hach, A . Pollard and A. G. Logan, Ther. Drug Monir., 1, 399 (1979). 52. J . D. Henion and G . A. Maylin, J . Anal. Toxicol., 4, 185 (1980). 53. P. P. Koopmans, Y. Tan, C. A. M. van Ginneken and F. W. J. Gribnau, J. Chromatogr.,
307, 445 ( 1984). 54. M. Yamazaki, Y. Ito, T. Suzuka, H. Yaginuma, S. Itoh. A. Kamada, Y. Orita, H.
Nakahama. T. Nakanishi and A . Ando, Chem. fharm. Bull., 32, 2387 2394 (1984). 55. B. Beermann, M. Groschinsky-Grind and A. Rostn, Clin. Pharmacol. Ther., 19, 531
(1976). 56. M. C. Meyer and P. L. Whyatt, J. Am. Pharm. Assoc., NS16, 47 (1976). 57. V. P. Shah, J. J . Lee, V. K. Prasad, J . P . Hunt and B. E. Cabana, Res. Commun. Chem.
58. I. J. McGilveray. R. D. Hossie and G. L. Mattok. Can. J. fharm. Sci., 8, 13 (1973). 59. M. C. Meyer, A. P. Melikian, P. L. Whyatt and G. W. A . Slywka, Curr. Ther. Res., 17.570
(1975). 60. B. Beermann, M. Groschinsky-Grind and B. Lindstrom, Eur. J. Clin. fharmacol., 11,203
(1977). 61. R . H. Barbhaiya, R. B. Patel. H . P. Corrick-West, R . S. J o s h and P. G. Welling,
Biopharm. Drug Dispos., 3 , 329 (1982). 62. New Drug Applications, Fed. Regist., 42. 1621 (1977). 63. K. A . Shah and T. E. Needham, J. fharm. Sci., 68. 1486 (1979). 64. L. L. Augsburger, R. F. Shangraw, R. P. Giannini, V. P. Shah, V. K. Prasad and D.
Brown, J. Pharm. Sci.. 72. 876 (1983). 65. B. Beerman and M. Groschinsky-Grind, Eur. J. Clin. Pharmacol., 13, 125 (1978). 66. R . H . Barbhaiya, W. A . Craig, H . P. Corrick-West and P. G. Welling, J . fharm. Sci., 71,
67. L. Backman, B. Beermann, M. Groschinsky-Grind and D. Hallberg, Clin. Pharmacokinet.,
68. E. Redalieu, K. K. H . Chan, V. Tipnis, S. B. Zak, T. G . Gillerman, W. E. Wagner Jr. and
69. B. Beermann and M. Groschinsky-Grind, Br. J. Clin. Pharrnacol., 7 , 579 (1979). 70. B. Beermann and M. Groschinsky-Grind, Eur. J. Clin. Pharmacol., 13, 195 (1978).
Biopharm. Drug. Dispos., 5, 55 (1984).
(1958).
fsychopharmacol. Commun., 2, 273 (1976).
Ther., 22, 225 (1977).
1309 (1975).
(1976).
Pathol. Pharmacol., 39, 39 (1983).
245 (1982).
4, 63 (1979).
A. R. LeSher, J. fharm. Sci., 74, 765 (1985).
534 PETER G . WELLING
71. 72.
73.
74. 75.
76. 77.
78. 79. 80. 81.
82.
83.
84. 85.
86.
87. 88.
89. 90.
91.
92.
93. 94.
95.
96. 97. 98.
99.
100.
101.
102.
103. 104.
105.
106. 107.
B. Beermann and M. Groschinsky-Grind, Eur. J . Clin. Pharmacol., 12, 297 (1977). B. Beermann, L. FBhraeus, M. Groschinsky-Grind and B. Lindstrom, Gynecol. Obstet. Invest., 11, 45 (1980). B. A. Mulley, G . D. Parr, W. K. Pau, R. M. Rye, J. J. Mould and N. C. Siddle, Eur. J . Clin. Pharmacol., 13, 129 (1978). M. E. Miller, R. D. Cohn and P. H. Burghart, J . Pediarr., 101, 789 (1982). C. Niemeyer, G. Hasenfuss, U. Wais, H. Knauf, M. Schafer-Korting and E. Mutscher, Eur. J . Clin. Pharmacol., 74, 661 (1983). B. Beermann and M. Groschinsky-Grind, Eur. J . Clin. Pharmacol.. 13, 385 (1978). S. T. Chiang, G. R. White, T. Spangler, M. Davis, V. L. Pascucci and B. R. Walker, J . Cardiovasc. Cardiol., 6 , S771 (1984). 0. 1. Corrigan, R. F. Timoney and M. J. Whelan, J . Pharm. Pharmacol., 28,703 (1976). W. A. Phillips, J. M. Ratchford and J. R. Schultz, J . Pharm. Sci., 65, 1285 (1976). D. B. Hunninghake, S. King and K. LaCroix. Inf . 1. Clin. Pharmacol., 20, 151 (1982). M. Kraml, J. Dubuc, D. Dvornik, S. Patterson-Kreuscher, H. Perdue, T. Y . Lee and J . Mullane, Biopharm. Drug Dispos., 3 , 55 (1982). L. Jordo, G. Johnsson, P. Lundburg, B. A . Persson, C. G. Regardh and 0. Ronn, Br. J . Clin. Pharmacol., 7, 563 (1 979). A. Kher, J. P. Fillastre, J . B. Fourtillan, M. A. Lefebvre and I. Ingrand, Eur. J . Clin. Pharmacol., 27, 361 (1984). H. Sundquist, M. Antilla, A. Simon and J . W. Reich, J . Clin. Pharmacol., 8, 557 (1979). A. Roux, A. Le Liboux, B. Delhotal, J . Gaillot and B. Flouvat, Eur. J . Clin. Pharmacol., 24, 801 (1983). A. Y . Chao, D. R. Sanvordeker, J . Zagarella, K. Mattes, B. Nicholova and A. Karim, J . Pharm. Sci., 65, 1630 (1976). H. Rameis, G. Hitzenberger and H. Horwatitsch, Inf. J . Chi . Pharmacol., 20, 327 (1982). R. L. Williams, R. 0. Davies, R. S. Berman. G. I. Holmes, P. Huber, W. L. Gee, E. T. Lin and L. Z. Benet, J . Clin. Pharmacol., 22, 32 (1982). H. Breithaupt and M. Tittel, Eur. J . Clin. Pharmacol., 22. 77 (1982). E. Keller, U. Sulzer, M. Brennes, P. Schollmeyer and G. Hoppe-Seyler, Klin. Woch., 59, 1223 (1981). P. J . Tannenbaum, E. Rosen, T. Flanagan and A. P. Crosley, Clin. Pharmacol. Ther., 9, 598 (1968). V. P. Shah, M. A. Walker, V. K. Prasad, J. Lin, G. Knapp and B. E. Cabana, Biopharm. Drug Dispos., 5 , 11 (1984). H. Knauf, W. Mohrke, E. Mutschler and K.-D. Volger, Arzneim.-Forsch., 30,1001 (1980). R. A. Upton, R. L. Williams, E. T. Lin, W. L. Gee, C. D. Blume and L. 2. Benet, J . Pharmacokinet. Biopharm., 12, 575 (1984). C. D. Blume, R. L. Williams, R. A. Upton, E. T. Lin and L. Z. Benet, Am. J . Med . , 77,59 (1984). C. D. Blume and R. L. Williams, Am. J . Med., 77, 52 (1984). N. M. Kaplan, Ann. Intern. Med., 102, 717 (1985). K. Felder, H. E. Geissler, S. Hiemstra, E. Mutschler, M. Schafer and E. Ziegler, Arzneim.-Forsch., 29, 1746 (1979). J. W. Poutsiaka, J. J . Piala, C. I. Smith, J. C. Burke and B. G. H. Thomas, J . Pharmacol. Exp. Ther., 128, 405 (1960). J. J . Piala, J. W. Poutsiaka, C. I. Smith, J. C. Burke and B. N. Craver, J . Pharmacol. Exp. Ther., 134, 273 (1961). B. Beermann, M. Groschinsky-Grind and B. Lindstrorn. Clin. Pharmacol. Thrr., 22, 385 (1977). M. Schafer-Korting, H. C. Korting, S. Hiemstra and E. Mutschler, Eur. J . Clin. Pharmacol., 23, 327 (1982). H. R. Bretell, J. G . Smith and J . K. Aikowa, Arch. Intern. Med., 113. 373 (1964). L. Borgstrom, C.-G. Johansson, H . Larsson and R. Lenander, J . Pharmacokinet. Biopharm., 9 , 431 (1981). B. Beermann, M. Groschinsky-Grind and B. Lindstrom, Acta Med. Scand , 204. 291 (1978). A. Agren and T. Back, Acta Pharm. Suecica., 10, 223 (1973). M. Schafer-Korting and E. Mutschler, Eur. I . Clin. Pharmacol.. 21, 315 (1982).
PHARMACOKINETICS OF THE THIAZIDE DIURETICS 535
108. B. Beermann, M. Groschinsky-Grind, B. Lindstrom and B. Wikland, Eur. J . Clin.
109. J. McAinsh, B. F. Holmes, N. S. Baber and J . Young, Biopharm. Drug Dkpos. , 2, 167
110. D. P. Nicholls, D . W. G. Harron, J . McAinsh, W. M. Castle, N. P. Barker and R. G.
111. 0. Bres, S. Jacobsen and E. Arnesen, Eur. J. Clin. Pharmacol., 11, 149 (1977). 112. R. B. Smith, R. V. Smith and G. J . Yakatan, J. Pharm. Sci., 65, 1208 (1976). 113. Y. Garceau, I. Davis and J . Hasegawa, J. Pharm. Sci., 63, 1793 (1974). 114. B. J . Owen and S. V. Wilke, 1. Pharm. Sci., 66, 877 (1977). 115. G. J . Yakatan, R. B. Smith, E. L. Frome and J . T. Doluisio, J. Clin. Pharmacol.. 17, 37
116. 0. Brers and S. Jacobsen, Eur. J. Clin. Pharmacol., 16, 125 (1979). 117. P. J . McNamara, W. A . Colburn and M. Gibaldi, J . Clin. Pharmacol., 18, 190 (1978). 118. 0. Brers and S. Jacobsen, Eur. J. Clin. Pharmacol., 15, 281 (1979). 119. 0. Brers, Acta Pharmacol. Toxicol., 51, 177 (1982). 120. 0. Brers, J. F. W. Haffner and S. Jacobsen, Eur. J. Clin. Pharmacol., 15, 287 (1979). 121. 0. Brers, S. Jacobsen and E. Arnesen, Eur. J . Clin. Pharmacol., 14, 29 (1978). 122. C. Piper, W. Cawello, R. Bonn and E. Weber, Arzneim.-Forsch., 33, 988 (1983). 123. R. R. Brodie, L. F. Chasseand, T. Taylor, D . A . O’Kelly and A. Darragh, J . Chromatogr.,
124. R. R. Brodie, L. F. Chasseand, A. Darragh, T. Taylor and L. M. Walrnsley, Biopharm.
125. M. C. Meyer and P. T. R. Hwang, J. Chromatogr., 223, 466 (1981). 126. H . Takahashi, Y. Watanabe, H . Shimamura and K. Sugito, J. Pharm. Sci., 74,862 (1985). 127. I. S. Sketris, V. A . Skoutakis, S. R. Acchiardo and M. C. Meyer, Eur. J . Clin. Pharmacol.,
128. D. C. Hobbs and T. M. Twomey, Clin. Pharmacol. Ther., 23, 241 (1978). 129. J . Dokladalova, S. 1. COCO, P. R. Lemke, G. T. Quercia and J. J . Korst, J. Chromatogr.,
130. R. Pinson, E. C. Schreiber, E. H . Wiseman. J. Chiaini and D. Baumgartner, J. Med.
131. R. V. Ford, Curr. Ther. Res., 3, 320 (1961). 132. R. M. Myerson, Curr. Ther. Res., 3, 431 (1961). 133. M. C. Meyer, P. Hwang and A . B. Straughn, Biopharm. Drug Dispos., 3, 1 (1982). 134. V. P. Shah, C. A. Keys, D. M. King, V. K. Prasad and B. E. Cabana, Biopharm. Drug
135. W. A. Forrest, Curr. Med. Res . , 6, 559 (1980). 136. M. J . Kerr, D . W. G. Harron, C. Kinney and R. G. Shanks, Br. J . Clin. Pharmacol., 12.
137. M. Stopp and H . Braunlich, Acra Biol. Med. Ger., 34, 89 (1975). 138. M. Stopp. C. Weise, S. Mewes and H. Braunlich, Acta B i d . Med. Ger . , 35, 787 (1976). 139. R. Storch and H . Braunlich, Acta Biol. Med. Ger. , 36, 237 (1977).
Pharmacol., 13, 119 (1978).
(1981).
Shanks, Br. J. Clin. Pharmacol., 14, 727 (1982).
(1977).
146, 152 (1978).
Drug Dispos., 3, 361 (1982).
20, 453 (1981).
224 33 (1981).
Chem., 5, 491 (1962).
Dkpos., 3, 283 (1982).
869 (1981).