P-Chlorophenyl Methyl Sulfide, p-Chlorophenyl Methyl Sulfoxide, and p-Chlorophenyl Methyl Sulfone. III. Toxicokinetics and Metabolism in Rats and Rhesus Monkeys

Abstract

Pharmacokinetic properties of p-chlorophenyl methyl sulfide, p-chlorophenyl methyl sulfoxide, and p-chlorophenyl methyl sulfone were evaluated in rats and rhesus monkeys following oral administration of 14C radiolabeled test materials. In addition, urinary metabolite formation in treated rats was partially assessed, as was microsomal enzyme induction as determined by hexobarbital sleep time assays. All test materials were found to be rapidly absorbed following gavage dosing with a biphasic diminution of blood radiolabel in the rat. As an apparent result of higher dosage levels, rhesus monkeys exhibited both a delayed attainment of peak blood levels and a lower rate of elimination of blood 14C. A minor portion (5–7%) of urinary radioactivity from treated rats was not extractable with chloroform until incubation with deconjugation enzymes was conducted, releasing up to 50%. The values for rhesus monkeys were 15–62% and 50%, respectively; the former values are apparently elevated (relative to rat) due to saturation of conjugate-formation pathways. Decreases were observed for hexobarbital sleep times following 3-day treatment with 50 mg/kg of each of the test compounds and, consistent with hepatomegaly observed in subchronic studies, suggest induction of hepatic microsomal enzymes. The study supports evidence that these chemicals are cleared primarily via the urine in a dose-dependent manner, and are conjugated to water-soluble metabolites in both rats and rhesus monkeys.