Effects of cimetidine and diethylaminoethyl 2,2-diphenylvalerate HCL (SKF 525-A) on trimethadione metabolism in the rat.
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.
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004114:Dimethadione / Q000097:blood; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010080:Oxazoles / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014293:Trimethadione / Q000378:metabolism*
D010080:Oxazoles; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D004114:Dimethadione; D014293:Trimethadione