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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 (T1/2), 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 (Vd) of TMO was not changed. The activities of hepatic cytochrome P-450-dependent drug-oxidizing 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.
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