ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1585040
Impact of CYP3A4 Functional Variability on Ziprasidone Metabolism
Provisionally accepted
- 1Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
- 2Wenzhou Medical University, Wenzhou, China
- 3Shaoxing People's Hospital, Shaoxing, Zhejiang Province, China
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This study investigated the functional variability of CYP3A4 in ziprasidone metabolism, focusing on drug-drug interactions and genetic polymorphisms. In vitro experiments using rat liver microsomes (RLM), human liver microsomes (HLM), and human recombinant CYP3A4 assessed metabolic inhibition and kinetic characteristics, while in vivo validation was performed in Sprague-Dawley rats. The results demonstrated that quercetin significantly inhibited ziprasidone metabolism in vitro, and in vivo coadministration led to marked increases in ziprasidone’s AUC(0-t), AUC(0-∞), CLz/F, and Cmax. Inhibition followed mixed mechanisms in RLM, HLM, and CYP3A4.1 systems. Further analysis of CYP3A4 genetic variants revealed differential metabolic efficiency: CYP3A4.3, 15, and 33 exhibited elevated clearance rates, whereas CYP3A4.24, 31, and 34 showed reduced activity. Quercetin’s inhibitory potency also varied across isoforms, with IC50 values of 17.59 ± 1.01 μM (CYP3A4.1) and 54.51 ± 1.35 μM (CYP3A4.33). Molecular docking identified ARG106, PHE108, PHE215, THR224, and GLU374 as key residues mediating inhibition. In conclusion, quercetin-mediated CYP3A4 inhibition and CYP3A4 genetic polymorphisms significantly influence ziprasidone metabolism.
Keywords: Ziprasidone, Quercetin, Drug-Drug Interaction, CYP3A4, LC-MS/MS
Received: 28 Feb 2025; Accepted: 10 Apr 2025.
Copyright: © 2025 Zhou, Wu, Ye, Zhang, Zheng, Qian, Xiao and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jianchang Qian, Wenzhou Medical University, Wenzhou, China
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