Pharmacokinetics of the Chemopreventive Agent Oltipraz and of Its Metabolite M3 in Human Subjects after a Single Oral Dose
2000
The dithiolethione oltipraz (OPZ) has activity as a chemopreventive
agent in animal models and is in early clinical trials. OPZ undergoes
metabolism by molecular rearrangement to yield a pyrrolopyrazine
derivative, M3, which we have previously shown to be inactive in the
induction of detoxication genes. M3 is metabolized further: at least 10
possible conjugates have been described in three species. We developed
a new high-performance liquid chromatography method to simultaneously
measure plasma concentrations of OPZ and of M3. This method was applied
to serial plasma samples in a Phase I clinical trial, in which OPZ was
administered at single doses varying from 125 to 1000
mg/m 2 . OPZ and M3 concentration-time profiles were highly
variable among individuals, and the occurrence of secondary
concentration peaks suggested substantial enterohepatic cycling.
Absorption was rapid, and the mean time to peak was 2.2 h. Maximum
plasma concentration values were proportional to the dose. Harmonic
mean half-lives at these doses ranged from 9.3–22.7 h. There were
indications of dose-dependent pharmacokinetic properties because
apparent clearance and volume of distribution at steady state increased
with dose, although these changes were not statistically significant as
a result of high interpatient variability. Accordingly, there were less
than proportional increases in the OPZ and M3 area under the curve and
maximum plasma values. Interpretation of OPZ and M3 disposition is
confounded by the unknown bioavailability factor; however, the most
likely inferences are that bioavailability of OPZ decreases with
increasing dose and that metabolism to M3 is saturable.
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