Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil

Abstract

Diltiazem and verapamil were found to be inhibitors of the cytochrome P-450-dependent biotransformation of drugs. Diltiazem and verapamil competitively inhibited the N-demethylation of aminopyrine in hepatic microsomes with Ki values of 100 and 140 microM respectively. Both diltiazem and verapamil were N-demethylated themselves by hepatic microsomes with Km values of 62 and 145 microM respectively. Both drugs also interacted directly with cytochrome P-450 as measured by difference spectra. Diltiazem caused a type I spectral change and verapamil caused a reverse type I spectral change. No metabolic intermediate complexes could be demonstrated for either drug. Inhibition also occurred in vivo as both drugs could prolong pentobarbital-induced sleeping times in mice at doses comparable to those used in man. These results suggest that diltiazem and verapamil may have the potential to cause drug interactions involving inhibition of drug biotransformation.