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 levels was evaluated. Pharmacokinetic analysis revealed nonlinear disposition of oltipraz with disproportionate 40-fold increase and 9.5-fold decrease in peak plasma concentrations (Cmax) and p.o. clearance, respectively, over the dose range of 100-500 mg. There was no correlation between the oltipraz dose and the absorption rate or the time to reach Cmax. Since oltipraz 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 levels over baseline in lymphocytes of subjects receiving 100 mg and 125 mg oltipraz. 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 correlation between oltipraz Cmax and the corresponding GSH and GST elevations. Subjects with higher Cmax values showed a greater increase over baseline in the GSH and GST levels. Mild toxicities were observed at all dose levels. The most common were flatulence, hunger, fatigue, and headache. These preliminary results indicate that oltipraz may be effective in inducing GSH and GST, an enzyme capable of carcinogen elimination.