pharmacokinetics and pharmacodynamics of oltipraz...

Vol. 1, 1133-1138, October 1995 Clinical Cancer Research 1133

Pharmacokinetics and Pharmacodynamics of Oltipraz as a

Chemopreventive Agent’

Elora Gupta, Olufunmilayo I. Olopade,

Mark J. Ratain, Rosemarie Mick,

Theresa M Baker, Frances K. Berezin,

Al B. Benson III, and M. Eileen Dolan2

Section of Hematology/Oncology, Department of Medicine [E. G.,

0. I. 0., M. J. R., R. M., T. M. B., F. K. B., M. E. D.], Committeeon Clinical Pharmacology [M. J. R., R. M.], Committee on Cancer

Biology [0. I. 0., M. E. D.], and Cancer Research Center [0. I. 0.,

M. J. R., R. M., T. M. B., M. E. D.], The University of Chicago,Chicago, Illinois 60637, and Division of Hematology/Oncology,

Department of Medicine [A. B. B.], Northwestern University,

Chicago, Illinois 60611

ABSTRACT

Oral oltipraz, as a single-dose treatment, was evaluated

as a chemopreventive agent in 31 normal subjects. In a

subset of subjects, the relationship between plasma oltipraz

concentrations and the induction of lymphocyte glutathione

(GSH) and glutathione S-transferase (GST) enzyme bevelswas evaluated. Pharmacokinetic analysis revealed nonlinear

disposition of oltipraz with disproportionate 40-fold increase

and 9.5-fobd decrease in peak plasma concentrations (Cmax)

and p.o. clearance, respectively, over the dose range of100-500 mg. There was no correlation between the oltipraz

dose and the absorption rate or the time to reach Cmax#{149}Since

obtipraz undergoes extensive metabolism, saturable first-pass elimination could be one of the sources of nonlinearity.

Pharmacodynamic evaluation was conducted based on the

percentage of elevation of GSH and GST bevels over baseline

in lymphocytes of subjects receiving 100 mg and 125 mg

obtipraz. Induction was observed in both dose groups with a

time lag between the maximum concentrations of oltipraz

and that of GSH or GST. We also observed a linear corre-

lation between oltipraz Cm�,, and the corresponding GSH

and GST elevations. Subjects with higher Cm,,,, valuesshowed a greater increase over baseline in the GSH and

GST bevels. Mild toxicities were observed at all dose levels.

The most common were flatulence, hunger, fatigue, andheadache. These preliminary results indicate that oltipraz

may be effective in inducing GSH and GST, an enzyme

capable of carcinogen elimination.

INTRODUCTION

Chemoprevention refers to the administration of agents to

inhibit various stages of carcinogenesis (1). Obtipraz3 belongs to

the class of 1,2-dithiole-3-thiones found in cruciferous vegeta-

bles. Epidemiobogical data suggest that consumption of crucif-

erous vegetables such as cabbage, broccoli, and brussel sprouts,

which are a source of 1,2-dithiole-3-thiones, results in decreased

cancer risk in humans (2, 3). Animal studies suggest that cab-

bage-supplemented diets protect against carcinogens by an in-

crease in the activities of a number of Phase II enzymes includ-

ing GST in conjunction with the elevation of intracellular GSH

levels (4-6). GSTs comprise a family of enzymes that can

conjugate potential carcinogens with GSH, resulting in in-

creased water sobubibity and elimination of the xenobiotics (7-

9). GSH is an important cellular nonprotein thiob, which has

been shown to serve as a protector against oxidants, free radi-

cabs, and ebectrophibic intermediates or certain chemicals includ-

ing drugs (10). Owing to its ability to induce GSH and GST

enzyme levels, obtipraz has shown efficacy as an inhibitor of

experimental carcinogenesis in breast, bladder, liver, forestom-

ach, colon, trachea, lung, and skin cancer in rodents (reviewed

in Ref. I 1). Thus, based on available data, oltipraz appears to be

a potential chemopreventive agent. However, there is limited

information on effective daily doses and toxicities of obtipraz in

humans.

Modulation of GST activity has been identified as a drug

effect marker of obtipraz administration. Additionally, if modu-

lation of GST activity is found to relate to cancer incidence in a

particular target tissue, this may very well represent the primary

mechanism of obtipraz’s chemopreventive effect in that target

(12). Rao et al. (13) have demonstrated enzyme induction in the

tissues of rats treated with oltipraz. Elevation of Phase II en-

zymes has also been reported in murine hepatoma cells and in

human peripheral blood lymphocytes following oltipraz expo-

sure (14, 15). Lymphocytes are considered to be a reliable

surrogate tissue for detecting liver GST polymorphisms in hu-

mans (16). Elevation of GST and GSH levels in lymphocytes

may serve as surrogate markers for relevant chemopreventive

pharmacodynamic activities of obtipraz in other target organs, if

modulation in lymphocytes is predictive of modulation in other

relevant target organs, and is validated in future trials addressing

this issue.

The goals of this study were to: (a) characterize the phar-

macokinetics of obtipraz following single p.o. doses, (b) inves-

Received 3/6/95; revised 6/2/95; accepted 6/8/95.

1 This work has been supported in part by the NIH through National

Cancer Institute Contracts NO1-CN-85103 and NO1-CN-25527

(A. B. B., 0. I. 0., M. J. R., M. E. D.), Grant CA-14599, and throughGeneral Clinical Research Center Grant MOl RR0055.

2 To whom requests for reprints should be addressed, at Section ofHematology/Oncology, The University of Chicago, 5841 South Mary-

land Avenue, MC 2115, Chicago, IL 60637.

3 The abbreviations used are: Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-

dithiole-3-thione; GST, glutathione S-transferase; GSH, glutathione;

NIST, National Institute of Standards and Technology; AUC, area under

the plasma concentration time curve; Cmax, maximum concentration;

Tmax, time to reach maximum concentration; CL,,, apparent p.o. clear-

ance; CV, coefficient of variation.

Research. on June 10, 2018. © 1995 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

http://clincancerres.aacrjournals.org/

% Elevation = x 100

1134 Clinical Evaluation of Oltipraz as a Chemopreventive Agent

tigate the induction of GSH and GST in lymphocytes, and (c)

evaluate toxicity associated with a single p.o. dose of oltipraz.

PATIENTS AND METHODS

Subjects. Normal subjects from the University of Chi-

cago volunteer program were chosen. The subjects had no

previous chemotherapy, immunotherapy, or radiation therapy,

were at beast 20 years of age, and had an Eastern Cooperative

Oncology Group performance status of 0. The subjects had no

serious renal, pulmonary, hepatic, or cardiac problems and were

not glucose-6-phosphate dehydrogenase deficient. Pregnant

women were excluded from the study. Informed written consent

was obtained from all subjects in accordance with institutional

and federal guidelines.

Treatment. A pilot study to determine pharmacokinetics

following p.o. administration of obtipraz involved 15 patients at

dose levels of 125-500 mg. A more thorough investigation

followed which included 16 patients at a dose of 20-125 mg,

and both pharmacokinetics and pharmacodynamics were eval-

uated. Oltipraz capsules (RP 35972) were formulated by Rh#{244}ne-

Poulenc (Paris, France) and were supplied by Ogden Bioser-

vices (in 20, 50, 100, and 125 mg strengths). Subjects were

admitted to the University of Chicago Clinical Research Center

for the duration of the study. Oltipraz was administered as a

single p.o. dose following a high-fat breakfast. This was done

because the bioavailabibity of oltipraz is markedly enhanced by

the coadministration of food, and a high-fat meal could further

improve the systemic availability (17-19).

Blood samples (7-10 ml each) were collected before drug

administration and at 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after

dosing. For the second investigation, additional blood samples

(20-30 ml) were collected at predose and at 6, 10, and 24 h after

drug administration to measure GSH and GST bevels.

Sample Analysis. To quantitate oltipraz in plasma sam-

pbes, a modification of the extraction method published by

Bennett et a!. (20) was used. One hundred jib plasma were

spiked with 50 jib internal standard (ethyl oltipraz, 4 jig/mb;

Rh#{244}ne-Poulenc) and extracted twice with 3 ml heptane. After

centrifugation, the supernatant (-5.5 ml) was evaporated to

dryness under nitrogen. The samples were reconstituted with

40% methanol and analyzed by reversed phase HPLC using a

jiNovapak C18 column (10 jim, 3.9 X 300 mm; Waters Asso-

ciates, Milford, MA). The mobile phase consisted of 60% meth-

anol:40% 50 mM ammonium acetate. The amount of oltipraz

in the samples was quantitated by monitoring absorbance at

448 nm. Adequate measures were taken during sample extrac-

tion procedures to prevent exposure to light. Extraction effi-

ciency was determined to be >90%, and all samples were

analyzed in duplicate. Standards from the NIST were also ana-

lyzed. There was less than 5% deviation between the actual

concentrations versus those determined by our methods, which

were acceptable by NIST.

For the quantitation of GSH, lymphocytes were isolated by

adding 30 ml blood to an equal volume of RPMI 1640 medium

and layered on Ficolb-Paque as described (21). After centrifu-

gation at 400 x g for 30 mm, the layer containing lymphocytes

was removed and resuspended in 15 ml PBS and centrifuged at

400 X g for 10 mm at room temperature. Resuspension in PBS

and centrifugation were repeated twice. Final pellets were sus-

pended in 0.1 M potassium phosphate buffer (pH 6.65). GSH

was measured using the glutathione disulfide reductase methods

of Tietze (22) and Griffith (23). Following two repeated 10-s

sonications of the lymphocytes in phosphate buffer, separated

by 30 5, sulfasalicyclic acid (1.7%; Sigma Chemical Co., St.

Louis, MO) was added. The samples were placed on ice for 10

mm and centrifuged at 500 X g for S mm at 4#{176}C.The super-

natant was incubated with NADPH, 5,5’-dithiobis(2-nitroben-

zoic acid), and glutathione reductase (Sigma Chemical Co.) in

sodium phosphatefEDTA buffer (pH 7.5). Glutathione reductase

was added immediately prior to reading at 412 nm. Results were

compared to standard curves constructed using increasing con-

centrations of GSH in place of lymphocyte extract in the reac-

tion mixture. Protein estimations were done according to the

method of Bradford (24).

Total GST in the lymphocytes was determined using a

kinetic spectrophotometric assay (25). Frozen lymphocyte peb-

lets were rapidly thawed, resuspended, and sonicated twice at

15-s intervals. Supernatant was obtained following centrifuga-

tion at 10,000 x g at 4#{176}Cfor 30 mm. Reaction mixtures

contained 500 jiM GSH, cytosobic extract (300 jig total protein),

and 3.2 mM 1-chboro-2,4-dinitrobenzene (Eastman Organic

Chemicals, Rochester, NY) in 0.01 M potassium phosphate

buffer (jH 6.65). The reaction was performed in a cuvette, and

the increase in absorbance was monitored at 0.25-mm intervals

for 2.5 mm. GST activity was determined as the linear rate of

formation of substrate. Protein estimation was performed ac-

cording to the method of Bradford (24).

Pharmacokinetic Analysis. Plasma concentration-time

data of oltipraz were analyzed by noncompartmental methods

using PCNONLIN (SCI Software, Lexington, KY). Estimates of

Cmax and Tmax were obtained from visual evaluation of the

plasma profile. AUC from time 0 to the last sampling time point

(AUC,) was calculated using the trapezoidal rule. The AUC

extrapolated to time infinity (AUC�...�) was estimated by divid-

ing the last quantifiable concentration by the terminal rate

constant (K) obtained by log linear regression of the terminal

phase. The total AUC was the sum of both the AUC estimations.

The terminal t112 was determined as the ratio of 0.693 to K. CL0

was calculated as the ratio of the dose to the total AUC. K,, was

determined by stripping the plasma concentration time profile

using RSTRIP (Micromath Scientific Software, Salt Lake City,

UT).

Pharmacodynamic Analysis. GSH Cm,,,, and GST Cmax

and the corresponding GSH Tm,,,, and GST Tmax were obtained

by visual evaluation of the lymphocyte GSH/GST concentra-

tion-time profile. The percentage of elevations at 6, 10, and 24 h

following p.o. oltipraz were determined using the following

equation:

Postdose bevel - Baseline

Baseline

Due to nondetectabbe plasma bevels of oltipraz following 20-

and SO-mg doses, pharmacokinetic-pharmacodynamic analyses

were performed for the dose levels of 100 mg and 125 mg only.



10000

1000

100

10

E

a,C

NJ

a-

F--J0 250 mg

125 mg

100 mg

0 3 6 9 12 15 18 21 24

HOUR

Clinical Cancer Research 1135

Fig. 1 Mean plasma profiles of p.o. oltipraz in healthy subjects. Asingle dose of oltipraz was administered following a high-fat breakfast,

and plasma samples were collected for a period of 24 h after dosing.

Points are represented as mean + SD. The number of subjects were 4,8, 4, 3, and 4 for the 100-, 125-, 250-, 375-, and 500-mg dose groups,

respectively. It should be noted that the pharmacokinetic parameter

estimates of Cmax and Tmax were determined from visual estimation ofindividual patient profiles. The means of these estimates are shown in

Table 1 and were not derived from the mean plots shown in this figure.

As a result, the numbers depicted in these plots are not identical to those

shown in Table I.

Toxicity Grading. Subjects were evaluated for acute

toxicity using standard National Cancer Institute toxicity crite-

na.

RESULTS

The average oltipraz plasma concentration over time fob-

lowing 5 different doses is shown in Fig. 1. Oltipraz concentra-

tions peaked at variable time points following administration.

Plasma concentration following doses of 20 mg and 50 mg were

below the limit of quantitation (-5 ng/ml). The observed con-

centrations resulting from all doses greater than SO mg were

higher than that reported in another investigation (19).

Nonlinearity was observed in the disposition of oltipraz.

The Cmax values showed a disproportionate 40-fold increase

over the 5-fold dose range, suggesting increased p.o. bioavail-

ability of obtipraz with increasing doses (Table 1). Accordingly,

there was a 44-fold increase in the AUC estimates (data not

shown), which resulted in a 9.5-fold decrease in the CL0 esti-

mates oven the dose range. Ka and Tmax values were unrelated to

the dose. While the Ka values ranged from 0.19 to 4.5 h ‘, the

Tmax values ranged from 0.5 to 8 h. Within each dose level, there

was a considerable amount of interpatient variability as mea-

sured by the CV percentage in the estimates of Cm,,,, (CV,

40-92%) and CL,, (CV, 31-71%).

Data from six patients, three from the 100-mg and three

from the 125-mg dose group, were obtained for pharmacody-

namic evaluation. For one patient receiving 125 mg obtipraz, the

enzyme levels at the 24-h time point could not be accurately

estimated. We observed intraindividual variability in the base-

line levels of GSH and GST. Since induction was measured

relative to baseline levels, we determined the extent of vaniabil-

ity I week before and on the day of dosing (prior to oltipraz

administration). The intrasubject CV in the GSH and GST levels

ranged from 2 to 9% and 1 to 29%, respectively, in the 100-mg

dose group and from 17 to 19% and 16 to 36%, respectively, in

500 mg the 125-mg dose group (Table 2).

375 mg Elevation of GSH or GST levels over baseline was ob-

served in both dose groups. Subjects showing elevation of GST

levels also tended to show induction of GSH levels. There

appeared to be a time lag between the plasma Cmax of oltipraz

and the lymphocyte Cmax of GSH or GST. The plasma and

lymphocyte profiles in a subject exhibiting the highest degree of

enzyme induction (subject 1, receiving 125 mg obtipraz) is

shown in Fig. 2. Overall, peak elevations in GSH bevels and

GST activity in lymphocytes occurred as early as 6 h after

dosing, although in many instances, peak levels/activities were

noted at the final sampling time (24 h), indicating that the Tmax

associated with these parameters may not have been realized in

this trial (Table 2). The response was dose dependent, with the

maximum induction of GSH levels in the 100-mg (subject 2)

and 125-mg (subject 1) dose groups being 27 and 81%, respec-

tively, while that observed in the GST levels was 60 and 101%,

respectively.

We investigated the correlation between the obtipraz Cmax

estimates and the corresponding GSH or GST percentage of

change. This was done because GSH and GST induction come-

bated better with oltipnaz Cmax than AUC estimates (data not

shown). As apparent from Fig. 3, subjects with higher oltipraz

Cmax values had a greater induction of GSH and GST. The

intrapatient variability (% CV) in the subject with the maximum

induction (patient 1, 125-mg dose) was 18% for GSH and 36%

for GST. In comparison, the maximum enhancement in GSH

was 81% whereas GST increased to 101%, indicating that it is

unlikely that these increases were due to variability in the data.

Toxicities observed were minimal and resolved without

any intervention. As shown in Table 3, side effects were not

dose related. In the first study, there were no toxicities at the

125-mg and 500-mg dose. In the second study, toxicities were

not observed at the 20-mg dose but were noted at 50, 100, and

125 mg. Most common toxicities were flatulence, hunger, fa-

tigue, and headache.

DISCUSSION

There have been a few studies reporting the dose-effect

relationship of obtipraz in humans (19, 26). The current inves-

tigation was designed to ascertain the pharmacokinetics of olti-

praz following a single p.o. dose and its enzyme induction effect

using lymphocyte GSH and GST as drug effect markers.

Obtipraz concentrations reported in this investigation have

been validated against NIST standards. The difference in values

compared to other studies could be due to variations in formu-

bation, diet, or subject characteristics (gender, body mass index,

metabolic capacity, etc.). Obtipraz exhibited nonlinear disposi-

tion, which could be partly due to saturation of its metabolic

pathway. This drug has been shown to undergo extensive me-

tabobism. About 13 metabolites have been identified in the urine

of mice, monkeys, and humans (27, 28). In humans, oltipraz has

been shown to form a desulfurated metabolite, and two pheno-



1 136 Clinical Evaluation of Oltipraz as a Chemopreventive Agent

Table 1 Pharmacokinetic parameters following p.o. administration of oltipraz

Dose Cm.,x Tmax Ka Terminal t172 CL

(mg) (np/mb) (h) (h’) (h) (literlh/m2)

20 nd” nd nd nd nd

(n 4)50 nd nd nd nd nd

(a 4)

i()0 125 ± 50 5.50 ± 1.91 0.57 ± 0.33 4.16 ± 1.69 119 ± 45.8

(Pt = 4) (67-189) (4.0-8.0) (0.19-0.92) (2.51-6.53) (82.7-178)

125 267 ± 139 1.88 ± 1.13 1.37 ± 0.82 6.95 ± 3.94 99.7 ± 46.5

(n 8) (50-546) (1.0-4.0) (0.54-2.82) (2.32-15.1) (60.4-192)

250 1062 ± 827 2.0 ± 1.16 0.96 ± 0.86 6.45 ± 3.60 47.6 ± 34.5

(n 4) (288-2084) (1.0-3.0) (0.36-2.22) (3.33-11.7) (16.6-92.8)375 2608 ± 2387 3.33 ± 2.52 1.84 ± 2.29 9.01 ± 4.89 14.6 ± 4.53

(0 = 3) (1091-5359) (1.0-6.0) (0.34-4.47) (4.92-14.4) (9.38-17.2)

500 4970 ± 351 1 2.63 ± 1.70 0.55 ± 0.21 1 1.1 ± 2.59 12.6 ± 7.53

(n = 4) (1952-9493) (0.5-4.0) (0.25-0.70) (8.89-14.6) (3.63-19.6)

I’ Values are mean± SD with the range indicated in parentheses.

1’ nd, not detectable.

Table 2 Pharmacodynamic parameter estimates following oltipraz administration”

GSH GST

Baseline % Cm.1x Tmax Baseline % Cmax Tmax

Subject (nmol/mg) CV (nmol/mg) (h) (nmol/min/mg) CV (nmol/min/mg) (h)

10() mgI 15.64 3 15.88 10 191.2 1 180.2 24

2 11.75 9 14.86 24 165.8 29 264.8 10

3 11.54 2 13.85 6 130.4 15 184.0 24

125 mg1 8.18 18 14.77 10 52.08 36 104.7 10

2 10.77 17 11.58 24 144.3 16 155.7 63 14.47 19 19.29 10 144.8 16 204.9 10

I’ GSH and GST levels in lymphocytes were quantitated at predose and at 6, 10, and 24 h after oltipraz dose. % CV, intrasubject CV percentageof two baseline levels determined I week before and on the day treatment began.

types of obtipraz metabobizers have been identified (26). High-

saturable metabolic clearance of obtipraz suggests appreciable

first-pass elimination of the drug and may result in reduced

systemic bioavailability from p.o. dosing while attaining en-

hanced hepatic delivery above that anticipated from iv. drug

administration.

Analysis of the plasma concentration-time data indicated

wide variability in the Ka and Tmax estimates, which was in

agreement with a previous report (19). Since Ka values were not

dose dependent, transport of obtipraz across the gastrointestinal

mucosa probably does not involve any active transport mecha-

nism. The rate of gastric emptying determines the time taken for

a p.o. administered drug to reach the absorption site and the rate

of absorption (29). Various foodstuffs influence the secretion of

gastrointestinal hormones and thereby affect gastric motility,

which in turn could control formulation disintegration and sub-

sequent dissolution of the drug (30). In the present study where

obtipraz capsules were administered in the presence of food,

individual differences in gastric emptying and gastric motility

could have contributed to the variable Ka and Tm,,,, values.

Pharmacodynamic analysis of the present data demon-

strated that oltipraz induced GSH as well as GST levels in the

lymphocytes with the induction of GST being more pronounced

than that of GSH. An elevation of GSH and GST correlated

better with the Cmax of obtipraz compared to the systemic

availability, suggesting the requirement of a minimum effective

concentration for oltipraz activity. It is unknown what magni-

tude of increase in GSH or GST constitutes a clinical response

and what duration of increase is required. The pharmacody-

namic observations of the present data must be made cautiously

since they are derived from only six patients distributed among

two dose levels. In addition, baseline bevels of GSH and GST

display significant inter- and intraindividual variability which

could be due to the assay as well as differences in dietary

conditions between the two level assessments. Therefore, if the

pharmacodynamic interpretations offered in this trial are accu-

rate, in that lymphocyte bevels of GSH and GST activity are

consistently modulated by oltipraz, maintenance of a sustained

increase in GST activity and GSH levels might be achieved by

repeated p.o. dosing of 125 mg obtipraz. Of course, the impact of

this modulation on cancer risk remains to be validated.

None of the toxicities observed in this study were dose

limiting. The most frequent toxicities included flatulence, head-

ache, fatigue, and hunger, suggesting that oltipraz is well tober-

ated as a single p.o. dose. Although this is consistent with

previous animal as well as human studies (reviewed in Ref. 12),



OLTIPRAZ Cmcx �/ml

A- 200 #{149}

E � S � � �

S5*5% H�1 150 . 1t GSH

NJ 100 . /< .

� 5�. :#{149}�‘

� 61 � -5.

0 0 #{149} � OLTIPRAZ

c; � 12 18 24

HOUR

I I I I I

B- 200E

�; 150 � GsT

NI 100

< S

0� 50

I- S-J0 O�

16

14 a’E

12

E10 �

:i:U)

8c.�

6

0�

100 E

C

80 E

0 6 12 18 24 30

C,z

C,

I-zIiiC)

wa-

U)CD

wCDz.cC,

I-zLUC,

LUa.

I-U)CD

Fig. 3 Correlation of oltipraz Cm,,,, values and GSH and GST percent-

age of change in subjects treated with a single dose of either 1(X) mg or

125 mg. Subjects with high Cmax values tended to have greater induction

of GSH and GST.

0 LII1I I I I

0 6 12 18 24

HOUR

HOUR

Table 3 Toxicities associated with a single dose of oltipraz

Toxicity No. of patients Dose (mg) Grade

Diarrhea 1 250 1

Bloating I 250 2Flatulence 2 1(X) 2Hunger I

IlOt)250

I1

Decreased appetite I 50 2

Metallic taste 1 375 1

Hives 1 125 2

Fatigue 1

11

50

125250

2

11

Headache 1

11

50

125250

1

11

Fig. 2 Representative profiles of the effect of oltipraz on GSH levels

(A) and GST levels (B) in lymphocytes in a subject receiving a dose of

125 mg (subject I). Oltipraz plasma levels peaked 4 h after dosing while

GSH and GST levels peaked at 10 h.

the exacerbation of the toxicities on repeated dosing remains to

be determined.

Chemoprevention may be a useful alternative in the control

of cancer in tissues for which therapeutic intervention is rela-

tively ineffective. Key concepts related to the development of

cancer chemopreventive agents include (a) long-term adminis-

tration, (b) p.o. route of administration, and (c) matching of

toxic side effects to degree of cancer risk (31). Following

repeated p.o. doses at 125 mg/day for 6 months, oltipraz was

well tolerated with major toxicities being grade 2 rash, grade 1

headache and vision change, and grade 1 fatigue, none of which

were dose limiting (32). Mean plasma concentrations obtained

in this chronic dosing study were 282 ng/mb, which were higher

than the plasma concentrations that resullted in maximum ele-

vations in GSH and GST in the current study. If this dosing

schedule results in sufficient increase in GSH and GST to

potentially protect against carcinogenesis, then oltipraz may

meet the criteria required for an effective chemopreventive

agent. Additional clinical investigations are warranted.

ACKNOWLEDGMENTS

We are grateful to Xiaolin Wang and Maricruz DeLeon for their

excellent technical assistance.

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1995;1:1133-1138. Clin Cancer Res E Gupta, O I Olopade, M J Ratain, et al. chemopreventive agent.Pharmacokinetics and pharmacodynamics of oltipraz as a

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