Effects of cimetidine and ranitidine on trimethadione metabolism in the rat.
Pretreatment of rats with cimetidine (100 mg/kg, i.p.) resulted in a prolongation of TMO half-life, an increase in the area under the curve (AUC) and a decrease of clearance (Cl), whereas in the rats pretreated with ranitidine (120 mg/kg, i.p.), these parameters were not changed. The apparent volume of distribution (Vd) values were not changed by either of the drugs as compared to controls. Activities of hepatic cytochrome P-450-dependent metabolizing enzymes such as aminopyrine- and TMO N-demethylase and aniline hydroxylase activity were decreased by pretreatment of rats with cimetidine, whereas in the rats pretreated with ranitidine, these enzyme activities were not changed. Cytochrome P-450 contents were not changed by either of the drugs as compared to controls. The inhibition manner of aminopyrine- and TMO N-demethylase activities in the rats pretreated with cimetidine was noncompetitive. These results indicate, together with the previous findings, that cimetidine treatment inhibited TMO metabolism, but ranitidine did not.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D010080:Oxazoles / Q000378:metabolism*; D011899:Ranitidine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014293:Trimethadione / Q000378:metabolism*
D010080:Oxazoles; D002927:Cimetidine; D011899:Ranitidine; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D014293:Trimethadione