Gene Polymorphisms and Drug-Drug Interactions Determine the Metabolic Profile of Blonanserin

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabo-lism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A micro-somal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra -performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its me-tabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10,12,13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and am-lodipine were found to potently inhibit the metabolism of blonan-serin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half -maximal inhibitory concentration and enzymatic kinetics assay dem-onstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and fe-lodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-1), and Cmax of blo-nanserin increased. When amlodipine and blonanserin were com-bined, the Cmax of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodi-pine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin.