Effects of CYP3A4 variants and drug–drug interactions on the metabolism of fexinidazole

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-20 DOI:10.1016/j.bcp.2026.117730

Jinyu Hu , Haoxin Fu , Ruibin Li , Peiqi Wang , Jun Wu , Lu Cao , Chenjian Zhou , Ren-ai Xu

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Abstract

Fexinidazole is a ctirical treatment for Human African trypanosomiasis in Africa, but its metabolic characteristics are not fully understood. This study investigated the impacts of CYP3A4 genetic polymorphisms and (−)-epigallocatechin gallate (EGCG) on the metabolism of fexinidazole in vitro (rat liver microsomes (RLM), human liver mircosomes (HLM), and nine CYP3A4 variants) and in vivo (rat) models. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was utilized to quantify fexinidazole and its metabolites. The results showed that fexinidazole was metabolized mainly by CYP3A4, which was significantly modulated by CYP3A4 polymorphisms. In addition, EGCG significantly inhibited the metabolism of fexinidazole in both RLM (IC₅₀ = 8.02 ± 0.28 μM) and HLM (IC₅₀ = 9.97 ± 0.43 μM) via mixed-type inhibition mechanisms. In vivo, co-administration of EGCG significantly altered the pharmacokinetic parameters of fexinidazole, increasing the AUC and C_max by approximately 1.46 and 1.44-fold, respectively, while decreasing clearance (CL_z/F). Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time.

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CYP3A4变异及药物-药物相互作用对非昔硝唑代谢的影响。

非昔硝唑是非洲治疗人类非洲锥虫病的重要药物，但其代谢特性尚不完全清楚。本研究研究了CYP3A4基因多态性和(-)-表没食子儿茶素没食子酸酯（EGCG）在体外（大鼠肝微粒体（RLM）、人肝微粒体（HLM）和9种CYP3A4变体）和体内（大鼠）模型中对非昔那唑代谢的影响。采用超高效液相色谱串联质谱法（UPLC-MS/MS）对非昔硝唑及其代谢产物进行定量分析。结果表明，非昔硝唑主要由CYP3A4代谢，CYP3A4多态性显著调节非昔硝唑代谢。此外,EGCG显著抑制fexinidazole的新陈代谢都那么使用RLM (IC50 = 8.02 ±0.28  μM)和高级别(IC50 = 9.97 ±0.43  μM)通过混合型抑制机制。在体内，EGCG共给药显著改变了非昔硝唑的药动学参数，使AUC和Cmax分别增加了约1.46倍和1.44倍，同时降低了清除率（CLz/F）。此外，持续给药EGCG显著下调肝脏关键CYP450 （CYP3a1、CYP2d1/2、CYP2b1/2和CYP2c11）的蛋白和mRNA水平。本研究首次阐明了非昔硝唑的主要代谢途径，并报道了遗传多态性和药物EGCG对其代谢的影响。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.