title: Different effects of dihydropyridine calcium channel antagonists on CYP3A4 enzyme of human liver microsomes.
abstract: 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 μmol 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.
authors.affiliation: Department of Pharmacy, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213000, China. lysaxia@yahoo.com.cn
authors.forename: Zongling
authors.initials: Z
authors.lastname: Xia
authors.forename: Mingli
authors.initials: M
authors.lastname: Wang
authors.forename: Sulan
authors.initials: S
authors.lastname: Zou
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D065692:Cytochrome P-450 CYP3A Inhibitors; D004095:Dihydropyridines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human