Effect of Change of Hepatic Drug-Metabolizing Activity on Plasma Concentrations of Major Metabolites of the New Sleep Inducer 450191-S, a 1H-1,2,4-Triazolyl Benzophenone Derivative

Abstract

Plasma concentrations of the major metabolites of 450191-S, a new sleep inducer which is a 1H-1,2,4-triazolyI benzophenone derivative, were determined in rats. Under the HPLC conditions employed, several major metabolites were detected in plasma, and thus the plasma concentration-time profiles for these metabolites were checked in rats in various states. When the animals were pre-treated with high doses of 450191-S (200 or 600 mg/kg for 5 or 3 days, respectively) to induce hepatic drug-metabolizing enzymes, plasma concentrations of the metabolites after oral administration of a dose of 200 mg/kg of 450191-S decreased markedly depending on the induced enzyme activity. Pretreatment of rats with phénobarbital also caused decreased plasma levels of metabolites, which were almost the same as those in 450191 -S-pretreatment On the other hand, administration of beta-naphthoflavone to rats led to higher plasma levels of metabolites, and slower elimination compared with those in the control and 450191-S- or phenobarbital-pretreated rats. These results indicate that plasma levels of metabolites are regulated by the drug-metabolizing enzymes in the liver. It also suggests the participation of some specific forms of cytochrome P-450 In the biotransformation of 450191-S and its metabolites.