Abstract：
This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal 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 metabolite. 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 amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated 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 felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max 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 amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.
摘要：
本研究旨在评估细胞色素P4503A4（CYP3A4）基因多态性和药物相互作用对bronanserin代谢的影响。使用Bac-to-Bac杆状病毒表达系统制备人重组CYP3A4。建立了微粒体酶反应体系,使用Sprague-Dawley大鼠评估药物-药物相互作用。采用超高效液相色谱-串联质谱法检测布南色林及其代谢物的浓度。与野生型CYP34A比拟，CYP3A4.29对bronanserin的相对清除率显着增加到251.3％，而CYP3A4.4、5、7、8、9、10、12、13、14、16、17、18、23、24、28、31、33和34显着下降，范围从6.09%到63.34%。在153种测试药物中，尼莫地平,非洛地平,发现氨氯地平能有效抑制布洛南色林的代谢。此外，尼莫地平的抑制效力，非洛地平,氨氯地平随CYP3A4变体的不同而变化。半最大抑制浓度和酶动力学测定表明，尼莫地平在大鼠肝微粒体中对bronanserin的代谢无竞争性抑制，而非洛地平和氨氯地平在大鼠肝微粒体和人肝微粒体中均以混合方式抑制。当尼莫地平和非洛地平与布洛南色林合用时，血药浓度-时间曲线下面积（AUC）（0-t），AUC(0-∞)，布洛南色林的Cmax增加。当氨氯地平和布洛南色林混合使用时，blonanserinC的Cmax显著增加。绝大多数CYP3A4变体具有低的催化bronanserin的能力。联合服用尼莫地平，非洛地平,和氨氯地平,bronanserin的消除受到抑制。本研究为临床个体化应用布南色林提供了依据。重要声明：研究了代谢bronanserin的新型CYP3A4酶的酶动力学。CYP3A4.4、5、7-10、12-14、16-18、23-24、28、31、33和34对bronanserin的清除率显着降低，但随着CYP3A4.29增加。此外,我们建立了布兰色林的药物相互作用谱，其中尼莫地平，非洛地平,氨氯地平动力学表现出混合抑制作用。此外，与CYP3A4.1相比，CYP3A4.4和5的抑制效力降低。这项研究为个性化临床使用bronanserin提供了必要的数据。
