EFFECTS OF CIMETIDINE AND DIETHYLAMINOETHYL 2, 2-DIPHENYLVALERATE HCL (SKF 525-A) ON TRIMETHADIONE METABOLISM IN THE RAT

Abstract

The effects of cimetidine and diethylaminoethyl 2, 2-diphenylvalerate (SKF 525-A) on trimethadione (TMO) metabolism were examined in the rat. The pretreatment of rats with cimetidine (100 mg/kg, i.p.) or SKF 525-A (40 mg/kg, i.p.) resulted in a prolongation of half-life (T_1/2), an increase in the area under the curve (AUC) and a decrease in the total body clearance (CL) of TMO. However, the apparent volume of distribution (V_d) of TMO was not changed. The activities of hepatic cytochrome P-450-dependent drugoxidizing enzymes such as aminopyrine and TMO N-demethylase, and aniline hydroxylase activities were decreased by pretreatment of rats with cimetidine or SKF 525-A. Cytochrome P-450 contents were not changed. The inhibition of aminopyrine and TMO N-demethylase activities in the rat pretreated with cimetidine or SKF 525-A was noncompetitive. These results suggest that cimetidine and SKF 525-A inhibited TMO metabolism in a similar manner to the rat pretreated with their doses.