Different effects of dihydropyridine calcium channel antagonists on CYP3A4 enzyme of human liver microsomes

摘要

The present study investigated inhibitory effects of 1,4-dihydropyridines (1,4-DHPs) calcium channel antagonists (1,4-DHP-CCAs) on cytochromeP450 3A4 (CYP3A4) of human liver microsomes and further explored importance of 1,4-DHPs molecular structural descriptors. Partial Least Squares method was applied to probe the quantitative relationships between the 1,4-DHPs molecular structural descriptors and its inhibitory actions, which demonstrated that different 1,4-DHP-CCAs could inhibit CYP3A4 enzyme's activity differently. The K_i values of nicardipine, lercandipine, cilnidipine, nitrendipine, lacidi-pine, nifedipine, felodipine were 10.13,10.17,11.44,23.90, 29.34, 29.06 and 32.64 mumol L~(-1), respectively. It is suggested that the 1,4-DHPs molecular structural descriptors are the most important for its inhibitory effects based on the quantitative structure-activity relationship (QSAR) formula. The LogP was positively correlated to the K_i, whereas molecular weight and molecule volume were negatively correlated. It is concluded that analysis of K_i of 1,4-DHPs derivatives on the CYP3A4 activity may apply for the QSAR formula at the initial stage of clinical application of new drugs.