Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
J Pharmacol Exp Ther. 2024 Jan 2;388(1):190-200. doi: 10.1124/jpet.123.001767.
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), AUC, and of blonanserin increased. When amlodipine and blonanserin were combined, the 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.
本研究旨在评估细胞色素 P450 3A4（CYP3A4）基因多态性和药物相互作用对博兰色林代谢的影响。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系统，并使用 Sprague-Dawley 大鼠评估药物-药物相互作用。采用超高效液相色谱-串联质谱法检测博兰色林及其代谢物的浓度。与野生型 CYP3A4 相比，CYP3A4.29 对博兰色林的相对清除率显著增加至 251.3%，而与 CYP3A4.4、5、7、8、9、10、12、13、14、16、17、18、23、24、28、31、33 和 34 相比则明显下降，范围为 6.09%-63.34%。在测试的 153 种药物中，发现尼莫地平、非洛地平、氨氯地平可显著抑制博兰色林的代谢。此外，尼莫地平、非洛地平、氨氯地平对不同 CYP3A4 变体的抑制作用存在差异。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博兰色林的代谢呈非竞争性抑制，而在大鼠肝微粒体和人肝微粒体中，非洛地平和氨氯地平以混合方式抑制博兰色林的代谢。当尼莫地平与非洛地平与博兰色林合用时，博兰色林的血药浓度-时间曲线下面积（AUC）、AUC 和 增加。当氨氯地平和博兰色林合用时，博兰色林 C 的 AUC 显著增加。绝大多数 CYP3A4 变体对博兰色林的催化能力较低。尼莫地平、非洛地平、氨氯地平联合应用可抑制博兰色林的消除。本研究为博兰色林的个体化临床应用提供了依据。 意义陈述：研究了新型 CYP3A4 酶对博兰色林代谢的酶动力学。CYP3A4.4、5、7-10、12-14、16-18、23-24、28、31、33 和 34 对博兰色林的清除率明显下降，但 CYP3A4.29 则增加。此外，我们建立了博兰色林的药物相互作用谱，其中尼莫地平、非洛地平、氨氯地平的动力学表现为混合抑制。此外，与 CYP3A4.1 相比，它们的抑制作用随 CYP3A4.4 和 5 而降低。本研究为博兰色林的个体化临床应用提供了重要数据。
