Zhou Qi, Wu Yameng, Ye Zhize, Zhang Zheyan, Zheng Kai, Qian Jianchang, Xiao Zhongxiang, Lu Yang
Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
School of Pharmaceutical Sciences, Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Pharmacol. 2025 Apr 29;16:1585040. doi: 10.3389/fphar.2025.1585040. eCollection 2025.
Ziprasidone is primarily metabolized by CYP3A4, an enzyme with genetic variability and susceptibility to inhibition or induction. This study explored the functional variability of CYP3A4 in ziprasidone metabolism, focusing on drug interactions and genetic polymorphisms.
The metabolic inhibition and kinetic properties of ziprasidone were evaluated through in vitro experiments utilizing rat liver microsomes (RLM), human liver microsomes (HLM), and CYP3A4 baculosomes. In vivo validation studies were conducted in Sprague-Dawley rats.
Quercetin significantly inhibited ziprasidone metabolism in vitro, with in vivo coadministration led to marked increasing in ziprasidone's AUC, CLz/F, and Cmax. Inhibition followed mixed mechanisms in RLM, HLM, and CYP3A4.1 systems. Analysis of CYP3A4 variants revealed distinct metabolic efficiencies: CYP3A4.3, 15, and 33 exhibited elevated clearance, while CYP3A4.24, 31, and 34 showed reduced activity. Quercetin's inhibitory potency varied across alleles, with IC50 values of 17.59 ± 1.01 μM in CYP3A4.1 and 54.51 ± 1.35 μM in CYP3A4.33. Molecular docking identified ARG106, PHE108, PHE215, THR224, and GLU374 as key residues mediating inhibition.
The findings of this study underscore the critical role of quercetin-mediated CYP3A4 inhibition and CYP3A4 genetic polymorphisms in modulating ziprasidone metabolism.
齐拉西酮主要通过细胞色素P450 3A4（CYP3A4）代谢，该酶具有遗传变异性且易受抑制或诱导。本研究探讨了CYP3A4在齐拉西酮代谢中的功能变异性，重点关注药物相互作用和基因多态性。
通过利用大鼠肝微粒体（RLM）、人肝微粒体（HLM）和CYP3A4杆状病毒颗粒进行体外实验，评估齐拉西酮的代谢抑制和动力学特性。在Sprague-Dawley大鼠中进行体内验证研究。
槲皮素在体外显著抑制齐拉西酮代谢，体内联合给药导致齐拉西酮的AUC、CLz/F和Cmax显著增加。在RLM、HLM和CYP3A4.1系统中，抑制遵循混合机制。对CYP3A4变体的分析揭示了不同的代谢效率：CYP3A4.3、15和33表现出清除率升高，而CYP3A4.24、31和34显示活性降低。槲皮素的抑制效力在不同等位基因间有所不同，在CYP3A4.1中的IC50值为17.59±1.01μM，在CYP3A4.33中为54.51±1.35μM。分子对接确定ARG106、PHE108、PHE215、THR224和GLU374为介导抑制作用的关键残基。
本研究结果强调了槲皮素介导的CYP3A4抑制和CYP3A4基因多态性在调节齐拉西酮代谢中的关键作用。
