Phramacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose

The dithiolethione oltipraz (OPZ) has activity as a chemopreventive agent i n animal models and is in early clinical trials. OPZ undergoes metabolism b y molecular rearrangement to yield a pyrrolopyrazine derivative, M3, which we have previously shown to be inactive in the induction of detoxication ge nes. M3 is metabolized further: at least 10 possible conjugates have been d escribed in three species, We developed a new high-performance liquid chrom atography method to simultaneously measure plasma concentrations of OPZ and of M3, This method was applied to serial plasma samples in a Phase I clini cal trial, in which OPZ was administered at single doses varying from 125 t o 1000 mg/m(2). OPZ and M3 concentration-time profiles were highly variable among individuals, and the occurrence of secondary concentration peaks sug gested substantial enterohepatic cycling, Absorption was rapid, and the mea n time to peak was 2.2 h. Maximum plasma concentration values were proporti onal to the dose. Harmonic mean half-lives at these doses ranged from 9.3-2 2.7 h. There were indications of dose-dependent pharmacokinetic properties because apparent clearance and volume of distribution at steady state incre ased with dose, although these changes were not statistically significant a s a result of high interpatient variability, Accordingly, there were less t han proportional increases in the OPZ and M3 area under the curve and maxim um plasma values. Interpretation of OPZ and M3 disposition is confounded by the unknown bioavailability factor; however, the most likely inferences ar e that bioavailability of OPZ decreases with increasing dose and that metab olism to M3 is saturable.