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.