Effects of Cytochrome P450 enzymes and drug-drug interaction on donafenib metabo...

연구 요약

Effects of Cytochrome P450 enzymes and drug-drug interaction on donafenib metabolism: in vivo, in vitro and in silico.

Bioorganic chemistry 학술지에 발표된 이 연구는 Shen Y, Wu J, Cao L 외 연구팀이 수행하였습니다.

이 연구는 'Effects of Cytochrome P450 enzymes and drug-drug interaction on donafenib metabolism: in vivo, in vitro and in silico.'에 대한 과학적 분석을 제공합니다.

핵심 내용

This study systematically elucidated the metabolic characteristics of the hepatocellular carcinoma (HCC) therapeutic drug donafenib and its drug-drug interaction (DDI) with the antiviral agent arbidol. In vitro phenotyping assays using chemical inhibitors and recombinant CYP enzymes identified CYP3A4 as the primary enzyme catalyzing donafenib N-oxide formation. This was further confirmed by in vivo pharmacokinetic experiments in Cyp3a1/2 knockout rats, where AUC(0-t), AUC(0-∞) and t1/2 of donafenib were increased compared with wild-type rats. Additionally, the study was the first to report the effects of 8 CYP3A4 variants (CYP3A4.39-.46) on donafenib metabolism. Among these, 7 variants (except CYP3A4.42) had reduced metabolic catalytic activity compared to wild-type CYP3A4.1, and the intrinsic clearance (CLint) was 8.60%-97.89% of that of CYP3A4.1. Subsequently, the potential mechanism of enzymatic activity changes was investigated through molecular docking. Finally, the study found that arbidol significantly inhibited donafenib metabolism, where the half-maximum inhibitory concentration (IC50) value of arbidol was 3.16 ± 0.09 μM in rat liver microsome (RLM) and 36.38 ± 1.23 μM in human liver microsome (HLM), respectively. Animal studies have shown that the pharmacokinetics of donafenib were significantly altered following co-administration of arbidol in Sprague-Dawley rats. The results indicated that the AUC(0-t), AUC(0-∞) and Cmax of donafenib were increased by 1.19-, 1.05- and 0.54-fold, respectively. Moreover, Tmax was prolonged by 68.42%, while CLz/F was decreased by 53.85%. These results provided critical references for clinical dosage adjustment, facilitating personalized treatment and reducing the risk of adverse reactions.

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