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

作者：Xia, Zongling; Wang, Mingli^*; Zou, Sulan; Chen, Rong

来源：European Journal of Drug Metabolism and Pharmacokinetics, 2012, 37(3): 211-216.

DOI：10.1007/s13318-011-0076-3

• CytochromeP450 3A4
• Inhibition constant
• 1,4-Dihydropyridine calcium channel antagonists
• Quantitative structure-activity relationship

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, lacidipine, nifedipine, felodipine were 10.13, 10.17, 11.44, 23.90, 29.34, 29.06 and 32.64 mu mol 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.

• 出版日期2012-9
• 单位苏州大学