The role of individual forms of cytochrome P450 in drug metabolism in human liver microsomes
Human liver microsomal metabolism of nicardipine was investigated and compared to that of another dihydropyridine, felodipine, and to published results for other compounds belonging to this class of drugs. The metabolism of tamoxifen and two iododerivatives, idoxifene and 4-iodotamoxifen, were also investigated. Nicardipine metabolism by human liver microsomes was dissimilar to that of other dihydropyridines in several respects. For most dihydropyridines studied to date, conversion to the corresponding pyridine is the major metabolic pathway; the results from this study suggested that pyridine formation is not the major pathway of human liver nicardipine metabolism. The oxidation of most dihydropyridines in human liver microsomes is CYP3A-dependent. In this study, the results from correlation studies and inhibition experiments implicated only CYP3A in nicardipine metabolism, however, not to the same extent as for other dihydropyridines. N-demethylation is the major metabolic route for tamoxifen in human liver and is dependent on the activity of CYP3A. The results from this study suggested that CYP3A is not largely involved in the metabolism of idoxifene and 4-iodotamoxifen in human liver microsomes. Incubations of idoxifene with human liver microsomes resulted in the formation of two metabolites, neither of which could be identified. Correlation and inhibition studies indicated that CYP1A, 2C, 2D and 3A were not involved in idoxifene metabolism in human liver microsomes, although, there was some evidence to support CYP2A involvement. Incubation of 4-iodotamoxifen with microsomes resulted in the formation of up to four metabolites, two of which could be identified. The formation of N-desmethyl 4-iodotamoxifen, the second largest metabolite, appeared to be dependent on CYP3A in human liver microsomes. Correlation studies did not implicate any P450 in the other pathways of 4-iodotamoxifen metabolism in human liver microsomes.