Pharmacokinetics of Compound 58-112, a Potential Skeletal Muscle Relaxant, in Man

J C/in Pharmacol. 1984; 24:47-57.

January 1984 47

Pharmacokineticsof Compound58-112,a PotentialSkeletalMuscleRelaxant,in Man

FRANCIS L. S. TSE, Ph.D., JAMES M. JAFFE, Ph.D., andJEREMY G. DAIN, Ph.D. East Hanover, N.J.

Abstract: The pharmacoki netics of 4-[(3-methoxyphenyl) methyl]-2,2,6,6-tetramethyl-1 -oxa-4-aza-2,6-disilacyclohexane (Sandoz compound 58-112), a new chemical entitywith a unique myotonolytic effect, was studied in 12 healthy male volunteers whoreceived an oral dose of 50 or 100 mg of the ‘4C-labeled drug. Serial blood and breathsamples and complete urine and feces were collected for 120 hours after dosing. Allsamples were analyzed for total radioactivity while the blood and urine were also

assayed for unchanged compound 58-112. Measurable blood radioactivity levels wereobserved at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after

dosing. The absorption of the radioactive doses was complete and appeared linear inthe 50-100 mg range, as indicated by blood ‘4C levels that were proportional to thedose. The 50- and 100-mg doses also resulted in virtually identical excretion patterns,with 95 per cent of the administered radioactivity recovered within 9 hours, almostexclusively in the urine. However, the disproportionately higher blood concentrationsof unchanged compound 58-112 after the 100-mg dose could suggest saturablepresystemic metabolism in the liver. Simultaneous fitting of all data in the 1 00-mg dose

study to a pharmacokinetic model showed that unchanged compound 58-112 was

distributed into a central and a peripheral compartment and was eliminated entirely bymetabolism, the distribution and elimination half-lives being 0.5 and 3.9 hours, respec-tively. The metabolite(s) was distributed into one homogeneous space, and its eli mina-tion half-life was 0.1 hour, with a renal:fecal clearance ratio of -96:4.

S ANDOZ compound 58-112 hydrochloride,

4{(3-methoxyphenyl)methyl]-2,2,6,6-tetra-

methyl-1-oxa-4.aza-2,6-disilacyclohexane hy-

drochloride, is a new chemical entity with a

unique myotonolytic effect.’ The compound

is currently undergoing Phase I clinical

trials to establish its usefulness in control-

ling the manifestations of muscle spasms

as well as its possible utility in certain spas-

tic conditions. Preliminary tests in animals

have suggested that compound 58-112 pro-

duces skeletal muscle relaxation via both

spinal and supraspinal sites of action with

minimal sedative or hypnotic activity.

In the rat and dog (S. I. Bhuta, unpub-

lished data), oral doses of the drug are rap-

From the Drug Metabolism Section, Sandoz, Inc., East

Hanover, N.J. 07936.

idly and almost completely absorbed, fol-

lowed by extensive extravascular distri-

bution. Approximately 90 per cent of a dose

is excreted within 24 hours of administra-

tion, primarily as metabolites in the urine.

CH3

H, CH2 CH,

[‘4C]58-1 12 hydrochloride

HCI

The present study was undertaken to ex-

amine the pharmacokinetic characteristics

of compound 58-112 in humans following

single oral doses of 50 and 100 mg [‘4C158-

112. Blood and excreta were analyzed for

TSE, JAFFE, AND DAIN

48 The Journal of Clinical Pharmacology

total radioactivity as well as for unchanged

compound 58-112.

MethodsSubjects

Prior to implementation of this study, the

research protocol, including the curriculum

vitae of the principal investigator and the

consent form, was reviewed and approved

by the Institutional Review Committee,

Peninsular Testing Corp., Miami, Fla.

Twelve healthy male volunteers (19 to 38

years old, weighing 63 to 91 kg), whose

weight-height relationships were within 15

per cent of normal, participated in the study

after giving written informed consent.

Their vital signs and electrocardiograms

were within normal limits, and blood and

urine laboratory values were within 10 per

cent of the normal range based on an initial

physical examination. All subjects had a

history of regular daily bowel movements

and normal daily pattern of urinary

excretion.

Study Medication

Radioactive compound 58-112 hydro-

chloride, labeled with carbon 14 at the

methylene group of the benzyl moiety, was

prepared by the Synthetic Tracer Labora-

tory, Sandoz, Inc., East Hanover, N.J. The

product was shown to be chemically pure

by the identity of its infrared spectrum and

its melting point with those of an authentic

sample. The radiochemical purity was bet-

ter than 95 per cent as determined by the

inverse isotope dilution method. Using this

substance, two batches of [‘4C]58-112 hy-

drochloride tablets were prepared. Batch

No. H-02575, each tablet made to contain 50

mg 58-112 base and 250 tCi ‘4C, was used in

the 50-mg portion of the study. Batch No.

H-02576, prepared to contain 50 mg 58-112

base and 125 MCi ‘4C, was used in the 100-

mg portion of the study.

Experimental Design

The 12 subjects were assigned, according

to a predetermined randomization sched-

ule, to one of two groups of equal size, and

the medication was administered on an

open basis. Thus, six subjects received a

50-mg dose and the other six received a 100-

mg dose of [‘4C]58-1 12.

Dosing and Sample Collection

All subjects fasted for 8 hours before and

2 hours after drug administration. At 8:00

A.M. on the treatment day, each subject re-

ceived orally one or two 50-mg tablets as

designated, followed by 4 to 6 oz. water. At

72 hours after dosing, each subject received

a capsule containing 250 mg carmine red,

which served as a stool dye marker.

Blood samples (15 ml) were collected in

oxalated plastic tubes by venipuncture

immediately before and at 0.5, 1,2,3,4,6,9,

12,24,36,48,72,96, and 120 hours following

drug administration. The samples were

stored frozen until analysis.

Quantitative urine collections were ob-

tained from each subject for the 0-3, 3-6,

6-9, 9-12, 12-24, 24-36, 36-48,48-72, 72-96,

and 96-120 hour intervals. All urine col-

lected within an interval was mixed thor-

oughly and immediately frozen until assay.

All fecal specimens passed during the 0-24,

24-48, 48-72, 72-96, and 96-120 hour inter-

vals were collected in separate plastic bags

and immediately frozen.

A modification of the method of Fred-

rickson and Ono2 was used for measuring

‘4C02 in expired air. Breath samples (10

liters) from each subject were collected im-

mediately before and at 0.5, 1,2,3,4,6,9,12,

24,36,48,72,96, and 120 hours after dosing.

The time required to expire 10 liters air was

recorded, and expired air was collected in

sealed plastic bags containing 15 ml of a

12% ethanolamine in methanol solution.

The plastic bag was shaken vigorously for

approximately 30 seconds, after which the

contents were completely transferred to a

plastic vial. The vials were stored frozen

until analysis.

Analysis of Radioactivity

Radioactivity was measured in a liquid

scintillation spectrometer (Model 2450,

COMPOUND 58.1 12 PHARMACOKINE TICS

January 1984 49

Packard Instrument Co.). The urine and

breath samples were assayed directly by

counting aliquots in a scintillation cocktail

consisting of 2,5-bis-2-(5-tert-butylbenzoxa-

zolyl)thiophene in toluene (8.3 Gm/liter).

Aliquots of blood were air-dried and corn-

busted in a sample oxidizer (Model 306,

Packard Instrument Co.). Fecal samples

were freeze-dried before being homogen-

ized, and aliquots were weighed for com-

bustion. Dose preparations were assayed

by both the direct and combustion methods.

The quench correction and efficiencies of

the oxidizer and counter were determined

using ‘4C-labeled hexadecane of known

specific activity as an internal standard.The limit of sensitivity of the assay was

defined as twice the mean background

count. Gross sample counts below this level

were considered to be not significantly dif-

ferent from zero. Blood concentrations of

radioactivity were calculated as Mg equiv-

alents of compound 58-112 per milliliter,

while the amount of radioactivity excreted

was calculated as percentage of the admin-

istered dose.

Analysis of Unchanged Drug

Blood samples from the six subjects in

each dose group were pooled by time point

and were analyzed for [‘4C]58-112 using

high-performance liquid chromatography

and the principles of reverse isotope dilu-

tion. Similarly, cumulative (0-48 hour)

urine samples in each dose level were

pooled and assayed for unchanged drug.

To blood (30 ml) or diluted urine (10 ml) in

a separatory funnel was added 0.5 ml of a

nonradioactive compound 58-112 (carrier)

solution (3.2 mg/mI). After thorough mix-

ing, the sample was made basic (pH 9) by

the addition of 10 per cent sodium carbo-

nate and was extracted with 2 X 120 ml

ethyl acetate/chloroform (2:1, v/v). The or-

ganic layer was separated and evaporated

to dryness, and the residue was suspended

in 5 ml dilute hydrochloric acid. Extrane-

ous materials were removed by extraction

into 2 X 10 ml ethyl acetate/heptane (1:1,

v/v). The acidic aqueous remainder was

made alkaline with 10% sodium carbonate

and again extracted with 2 X 10 ml ethyl

acetate/heptane (1:1, v/v). After evapora-

tion of the organic solvent, the residue was

dissolved in 200 M’ methyl-tert-butyl

ether/isopropyl alcohol (30:0.4, v/v), and a

S#{176}-M1aliquot was analyzed on a Waters As-

sociates Radial Pak A silica gel column.

The mobile phase was heptane/methyl-

tert-butyl ether/isopropyl alcohol/triethyl-

amine (375:75:1:1) with a flow rate of 2

mi/mm, and detection was achieved with a

Perkin-Elmer LC-75 spectrophotometer

monitoring at 254 nm. The drug was sepa-

rated from the metabolites and interfer-

ences from the biologic matrix under these

conditions.

The peak area of compound 58-112 in the

chromatogram was measured. The eluant

containing the chromatographic peak of

58-112 was collected for a predetermined

fixed time interval in a scintillation vial

and counted for radioactivity. The concen-

tration of[’4CJ58-112 in the original blood or

urine was then determined using a stand-

ard curve constructed from the analysis of

[‘4C]58-112 of known specific activities. The

method was validated by analyzing sam-

ples containing a known concentration of

[‘4C]58-1 12. The overall coefficient of varia-

tion was 4.4 per cent, and it was determined

that a single assay would fall within ±15

per cent of the true value at 95 per cent

confidence level. The limit of sensitivity,

dependent upon the specific activity of the

drug used, was 0.85 ng/ml for the 50-mg

dose and 1.6 ng/ml for the 100-mg dose in

the present study.

Data Treatment

Visual inspection of semilogarithmic plots

of blood compound 58-112 levels versus

time indicated that the disappearance of

unchanged drug in blood was biexponen-

tial. Hence, assuming that the amount of

radioactivity in body not due to unchanged

compound 58-112 was disposed of as a

homogeneous group of metabolites, the

ka

IT

Fig. 1. Pharmacokinetic model of compound 58-1 12 in man following a

single oral dose. (See text for definition of terms.)

kf Af



data could be analyzed in terms of the com-

partmental model depicted in Fig. 1. Further

assumptions made in this model, supported

by laboratory data in the present study,

were that the dose was completely absorbed

and that the absorbed drug was completely

metabolized prior to its elimination in the

urine and feces. In Fig. 1, D is the dose of

[14C]58-1 12, LT is the lag time of absorption,

ka is the first-order rate constant of drug

absorption into a central compartment

having an apparent distribution volume

V,, and A, and A2 refer to the amounts of

unchanged drug in the central and pe-

ripheral compartments, respectively. The

first-order rate constants k,2 and k2, govern

the transfer of drug between compart-

ments, while km is the first-order rate con-

stant of metabolism. The total amount of

metabolite, M, is distributed in a homo-

geneous space Vm. The first-order rate con-

stants k and kf govern the excretion of me-

D

tabolite in the urine and feces, respectively,

RT is the residence time preceding fecal

excretion, and A and Af represent the re-

spective amounts of metabolite in urine and

feces.

The concentration of unchanged drug in

blood, C1, at any time t after a single dose is

described by eq. (1):

D . kak21 - k -k(t-LT)

eV1 (a-ka)($ka)

k21 - a -a(t-LT)

+(ka - a) ($ - a)

k21 - $ J+

(ka-$)(a-$) (1)

where a and /3 are composite rate constants

as defined previously.3

COMPOUND 58-112 PHARMACOKINE TICS

The concentration of metabolite in blood, Cm, as a function of time is defined by eq. (2):

Dkakm k21-k.Cm [ . ka(tLT)

Vm (a-ka)($-ka)(ke-ka)

k2, - a+

(k - a) (/3 - a) (ke - a)

k21 - /3+

(k. - /3) (a - /3) (ke - /3)

+ k2, - ke .

(kake)(ake)($ke) (2)

where k. represents the overall elimination rate constant for the metabolite, k + kf.

Accordingly, the concentration of total radioactivity in blood equals C1 + Cm.

Equation (3) describes the cumulative excretion of metabolite (total radioactivity) in the

urine:

AuDkmkuE k21

a- /3.

k21 -

________________________________ (ILT)

(a - k11) (/3 - k.) (k. - k.)

k5(k2, - a) . etI’)

a (k - a) (/3 - a) (k - a)

k(k2, - /3)e_mt_

k(a - k.) - e_t_LT)]

ke (k. - k.) (a - k0) (p - k) (3)

January 1984 51

Similarly, the amount of metabolite (total radioactivity) excreted in the feces is:

k21Af = D . km k,

a $ ke

ka(k21 - ke)

ke(kake)(ake)($ke)

e_t_lT_RT) I

(7)

D



k2, - k

(a - ka) (/3 - ka) (ke - k)

k.(k21 - a)

a(k-a)($-a)(k-a)

k(k2, - /3)

- /3) (a - /3) (k. - /3)

- e_t_.T_lm

et_IT_

e_at_LT_T)

(4)

Pharmacokinetic analysis was performed

using the mean data from the subjects who

received the 100-mg dose, which yielded

higher unchanged drug levels and there-

fore relatively well-defined blood profiles.

The use of mean data in describing phar-

macokinetic characteristics for the subject

population is adequate when intersubject

variability is small,4 as is the case in the

present study.

Initial estimates of pharmacokinetic pa-

rameter values were obtained by standard

graphic methods, while improved parame-

ter estimates together with statistical

analysis were obtained using the iterative

nonlinear regression program NONLIN.5

Blood levels of unchanged compound 58-

112 as well as the blood, urine, and feces

data on total radioactivity were fitted si-

multaneously to the appropriate equations.

The computer-generated parameter esti-

mates were subsequently used in the calcu-

lation of secondary pharmacokinetic pa-

rameters. The half-lives of drug absorption

(t#{189}abs), drug distribution (t#{189}a), drug elim-

ination (t#{189}/3), and metabolite elimination

(t#{189}rn) are the reciprocals of ka, a, /3, and ice,

respectively, multiplied by 0.693.6

The total volume of distribution of un-

changed drug at equilibrium, V, can be

calculated using eq. (5):

k,2V,,=V,(1+-) (5)

k21

The total body clearance TBC of un-

changed drug is described by eq. (6):

TBCV1km (6)

At equilibrium, the ratio of unchanged

compound 58-112 in the tissue compart-

ment to that in the central compartment,

T/P, is:

k12T/P =

k21 - /3

The area under blood concentration-

versus-time curve (AUC) for unchanged

drug can be determined by eq. (8):

AUC=- (8)TBC

It should be noted that in the present

model (Fig. 1), no distinction was made be-

14.8 ng/ml at 2 hours after the 100-mg dose.

Over the entire sampling period, unchanged

drug contributed 0.4 to 0.9 per cent of total

radioactivity in blood following the 50-mg

dose and 0.5 to 1.3 per cent following the

100-mg dose. Unchanged compound 58-112

blood levels fell below the limits of detection

at 4 and 9 hours after the 50- and 100-mg

doses, respectively.

The mean excretion of radiolabel in urine

and feces is summarized in Table III. Fol-

lowing the 50- or 100-mg oral dose, 45 to 50

per cent of the administered radioactivity

was excreted in the urine within 3 hours

and 96 to 100 per cent within 12 hours. Less

than 0.01 per cent of the radioactivity in the

0-48 hour urine was due to unchanged drug

following either dose. Including small quan-

titites of radiolabel in the feces, mean total

recoveries (0-120 hours) were 115 per cent of

the 50-mg dose and 111 per cent of the 100-

TABLE II

Blood Concentrations of Compound58-112 Following a Single Oral Dose of

[‘4C]58-1 12*

tween the hepatic-portal system and the

central compartment containing the vascu-

lar site sampled. Nevertheless, a reason-

able estimate of the first-pass effect can be

obtained from eq. (9), provided the dose of

[‘4CJ58-1 12 is completely absorbed7:

(9)

In eq. (9), f represents the fraction of ab-

sorbed dose that reaches the systemic circu-

lation intact, and Q is the hepatic blood

flow rate, 1.7 liter/mm.8

Results

No clinically significant side effects were

observed in the 12 subjects. Blood levels of

total radioactivity and unchanged com-

pound 58-112 are summarized in Tables I

and II, respectively. Maximum blood con-

centrations of radioactivity ranging from

0.51 to 0.69 g equiv./ml for the 50-mg dose

and from 1.01 to 1.59 g equiv./ml for the

100-mg dose occurred at 1 to 2 hours after

drug administration. The mean blood de-

cay curves from the two doses were virtu-

ally parallel; and by 24 hours after dosing,

blood radioactivity concentrations were

not significantly different from zero. As

shown in Table II, the concentrations of

unchanged compound 58-112 in blood were

relatively low, with mean peak values of 4.7

ng/ml at 1 hour after the 50-mg dose and

Blood concentration of compound

58-112 (ng/ml)Dose

(mg) 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 9 hr 12 hr

50 1.2 4.7 4.0 2.0 1.2 N.D. ND. N.D.

100 2.2 13.0 14.8 7.4 3.9 2.7 1.7 N.D.

* Each value represents pooled blood samples from six

subjects. ND. = Not detected.


January 1984 53

TABLE I

Blood Concentrations of Total Radioactivity (Mean ± S.D., N 6)

Following a Single Oral Dose of [‘4C]58-1 12

Dose Blood co ncentratio n of radioa ctivity (gig equiv. of c ompound 58-112/ml)

(mg) 0.5 hr 1 hr 2 hr 3 hr 4 hr 6 hr 9 hr 12 hr 24 hr*

50 0.16

± 0.11

0.50± 0.15

0.51

± 0.06

0.41

± 0.08

0.32± 0.05

0.19

± 0.05

0.09± 0.02

0.03

± 0.03

0

100 0.21

± 0.13

1.00

± 0.49

1.26

± 0.14

0.98

± 0.09

0.75

± 0.07

0.45

± 0.03

0.23

± 0.02

0.12

± 0.020

* Radioactivity concentrations were not significantly different from zero in all blood samples collected during

24-120 hours.

f= QQ + D/AUC

TABLE III

Excretion of Radioactivity (Mean ± S.D., N 6) Following a

Single Oral Dose of [‘4C]58- 112

Time

interval

(hr)

Per cent of dose

50mg 100mg

0-3

3-6

6-9

9-12

12-24

24-36

36-48

48-72

72-96

96-120

Urine

50.2 ± 11.6

30.2 ± 8.5

13.8 ± 3.9

5.5 ± 1.8

6.7 ± 2.0

1.5 ± 0.5

1.0 ± 0.8

0.5 ± 0.30.2 ± 0.1

0.1 ± 0.1

45.0 ± 22.6

29.5 ± 14.1

15.5 ± 10.3

6.3 ± 3.0

7.0 ± 2.1

1.2 ± 0.5

0.5 ± 0.1

0.5 ± 0.1

0.2 ± 0

0.2 ± 0.1

0-120 109.6 ± 6.1 105.8 ± 6.5

Feces

0-2424-48

48-72

72-96

96-120

0.5 ± 1.22.0 ± 1.4

1.4 ± 1.5

1.4 ± 2.1

0.2 ± 0.1

1.6 ± 2.11.0 ± 0.9

1.8 ± 2.5

0.4 ± 0.3

0.1 ± 0.1

0-120 5.4 ± 2.3 4.9 ± 2.7

Total in urine and feces 0-120 115.0 ± 5.2 110.7 ± 6.0



mg dose. No radioactive material was de-

tected in any of the exhaled air samples.

The results of pharmacokinetic and sta-

tistical analyses are given in Table IV,

while Figs. 2 and 3 show the computed

curves of blood levels and cumulative

amount excreted, respectively. The good-

ness of fit of observed data to the equations

was demonstrated by correlation coeffi-

cients of 0.95 to 1.00. Following a single

100-mg oral dose of[’4C]58-112 in man, the

drug was absorbed, after a 20-minute delay,

with a rate constant of 0.65 hr’, which cor-

responds to an absorption half-life of 1.07

hour. According to eq. (9), only 6 per cent of

the absorbed dose reached the systemic cir-

culation intact due to first-pass metabolism

in the liver. The distribution rate constants

k12 and lc21 and the metabolic rate constant

km were 0.57, 0.35, and 0.79 hf’, respec-

tively, representing half-life values of 0.45

hour for distribution and 3.85 hours for

elimination of unchanged drug. Preferen-

tial distribution of compound 58-112 into

the tissues was indicated by a T/P ratio of

3.35 at equilibrium. The volume of the cen-

tral compartment was 30.3 liters/kg, while

the total distribution volume at steady state

was 79.6 liters/kg, based on a mean body

weight of 72 kg. The total body clearance of

unchanged drug was 23.9 liters/hr/kg, and

the area under the blood level-time curve

was 58.1 ng/ml . hr. After its formation, the

metabolites distributed into a volume of

0.04 liter/kg. The urinary and fecal excre-

tion rate constants, 5.64 and 0.25 hf’, re-

spectively, indicated a metabolite elimina-

tion half-life of 0.12 hour. The residence

time prior to fecal excretion was estimated

to be 44 hours.

Discussion

Orally administered [‘4C158-112 in man

was absorbed after a lag time of 20 minutes

and reached maximum blood concentra-

1.0

0.8

0.4

0.015 0

0.010 [0.005 L

I I

0 3 6 9

0 2 4

COMPOUND 58-112 PHARMACOKINETICS

January 1984 55

TABLE IV

Pharmacokinetic Parameters Following aSingle 100-mg Oral Dose of[’4C158-112

Parameter Final estimate 95% confidence interval

k. (hr) 0.65 -0.36- 1.67

k0 (hr) 0.57 -0.34- 1.48

k21 (hr) 0.35 -0.01 -0.71Ic.,, (hrTh 0.79 -0.67- 2.26

Ic., (hr) 5.64 -5.10- 16.4

k1 (hr’) 0.25 -0.22- 0.72

V, (liters/kg) 30.3 -28.9- 89.4

V.,, (liters/kg) 0.040 -0.035 - 0.11

LT (hr) 0.33 0.19-0.46

RT (hr) 44.0 42.4 - 45.6

ti,2 abs (hr) 1.07

a (hr) 1.53t#{189}a (hr) 0.45

(hr) 0.18

t#{189}$ (hr) 3.85t#{189}m (hr) 0.12

V.. (liters/kg) 79.6

TBC (liters/hr/kg) 23.9

T/P 3.35

AUC (ng/ml hr) 58.1

f 0.056

Parameters defined in text.

Ii

1.4 r

0.6

0.2

0

6 8 10 12

Time (hr)

Fig. 2. Mean blood concentrations of total radioactivity (.) and unchanged

compound 58-112(o) following a single 100-mg oral dose of [‘4C]58.1 12 in six

subjects. The curves are computer-derived.

100

0

0

0 24 48 72 96 120

Time (hr)

Fig. 3. Mean cumulative excretion of radioactivity in the urine (.) and feces

(o) following a single 100-mg oral dose of [‘4CJ58-112 in six subjects. Thecurves are computer-derived.

-o 0



tions 1 to 2 hours after dosing. The calcu-

lated half-life of absorption following the

100-mg dose was 1.1 hour, which suggests

that better than 95 per cent of the dose was

absorbed within 5 hours of drug adminis-tration. Since only 5 per cent of the adminis-

tered radioactivity was recovered in the fe-

ces after both the 50- and 100-mg doses, it

can be concluded that the absorption of or-

ally administered compound 58-112 in this

dose range is virtually complete. Conse-

quently, 100 per cent absorption was as-

sumed in the compartmental model used for

pharmacokinetic analysis.

The absorbed compound 58-112 under-

went extensive presystemic metabolism, as

evidenced by the extremely low unchanged

drug levels compared to total radioactivity

in blood. It was subsequently distributed

into the tissues, with a distribution half-life

of 0.45 hour. Preferential tissue distribution

was indicated by the large distribution vol-

umes, 30.0 and 79.6 liters/kg, respectively,

for the central compartment and the overall

space at equilibrium. The tissue:blood ratio

of unchanged drug content was 3.35. In

contrast, the metabolites exhibited little

tissue affinity, with a volume of distribu-

tion of 0.04 liter/kg. Although computer

analysis was not performed for the 50-mg

study, it appears that the distribution pat-

tern of compound 58- 112 and its metabolites

may be dose independent within the 50- to

100-mg range, as indicated by the virtually

linear relationship between the dose and

total radioactivity concentrations in blood

throughout the sampling period. On the

other hand, unchanged compound 58-112

blood levels after the 50-mg dose were dis-

proportionately lower than those after the

100-mg dose, suggesting the likelihood of

saturable first-pass metabolism. As indi-

cated by the negligible amounts of un-

changed drug recovered in the urine after

both the 50- and 100-mg doses, compound

58-112 was completely metabolized prior to

its excretion. The elimination half-life of

unchanged compound 58-112 was 3.85 hours.

There was no difference in the excretion

of radioactivity between the 50-and 100-mg

doses, with approximately 50 per cent of the

administered radioactivity recovered within

the first 3 hours and 95 per cent within 9

hours after dosing. The total recovery in

urine and feces of more than 110 per cent

could possibly be the result of an experi-


January 1984 57

mental error in the analysis of the radioac-

tive dosage form, since the dose assay

values were used as references in calculat-

ing the percentage dose excreted. This con-

sistent error, however, would not affect the

overall results or conclusion of the study.

Curve fitting of the 100-mg dose data

showed that at infinity, 95.8 per cent of the

dose would be excreted in the urine and 4.2

per cent in the feces. The elimination half-life of the metabolites (0.12 hour) was short-

er than that of the unchanged drug (3.85

hours), indicating that the formation of the

metabolites, not their excretion, was the

rate-limiting step in the elimination of ra-

dioactive material from the body following

an oral dose of[14C]58-112.

In conclusion, single oral doses of 50 and

100 mg [‘4C]58-112 are 8afe and well toler-

ated. The drug is rapidly and completely

absorbed but is extensively metabolized be-

fore reaching the systemic circulation. The

first-pass effect appears saturable in thedose range studied. The relatively large vol-

umes of distribution indicate preferential

tissue uptake of compound 58-112 which is

completely metabolized prior to its excre-

tion. The administered radioactivity is

completely recovered within 24 hours after

dosing, predominantly in the urine.

Acknowledgments

The clinical portion of this study was con-ducted under the supervision of Albert Cohen,M.D., Peninsular Testing Corp., Miami, Fla., andJohn Gogerty, Ph.D., Clinical Research Depart-ment, Sandoz, Inc., East Hanover, N.J.

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07936.

Pharmacokinetics of Compound 58-112, a Potential Skeletal Muscle Relaxant, in Man

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