The Effect of Diltiazem and Verapamil on Hepatic Microsomal Drug Metabolizing Enzymes in Rat

Abstract

Diltiazem and verapamil, calcium channel blocking agents, are reported to elevate plasma concentrations of some clinically used drugs in humans. In the present study, the effect of diltiazem and verapamil on the hepatic mixed function-monoxygenase system was investigated in Sprague-Dawley rats. Diltiazem and verapamil significantly increased cytochrome P-450 content by 60.8% (p<0.01) and 51.3% (p<0.01), respectively, after 5 days of treatment compared to the control value. Content of cytochrome b5 was significantly increased by verapamil (45.3%, p<0.01) but not by diltiazem. Activity of aminopyrine-N-demethylase was significantly increased by 5 days of treatment with diltiazem (61.9%, p<0.01) and verapamil (47.8%, p<0.01) . Aniline hydroxylase activity was gradually increased by verapamil treatment with significance on day 5 (33.8%, p<0.05) . The serum ratio of dimethadione to trimethadione (DMO/TMO) was significantly increased by diltiazem (from 0.40 to 0.87, p<0.05), but not by verapamil treatment. Diltiazem significantly enhanced the amount of 4-hydroxyantipyrine excreted into urine from 8.8% to 24.5% (p<0.01) . There was no significant change of any antipyrine metabolite by verapamil treatment. Both diltiazem and verapamil significantly increased the debrisoquine/4-OH debrisoquine ratio indicating inhibition of debrisoquine metabolism. These results suggest that both diltiazem and verapamil induce cytochrome P-450 but have different effects on the activity of P-450 isozyme in rats. Inhibition of hepatic drug-oxidizing enzymes by diltiazem and verapamil reported in humans was observed in this study of the metabolism of debrisoquine in rats.