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Toxicology

Toxicology

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Drug-induced enzyme activity inhibition and CYP3A4 genetic polymorphism significantly shape the metabolic characteristics of furmonertinib

Published:3 August 2024 DOI: 10.1016/j.tox.2024.153903 PMID: 39098371
Qi Zhou , Zhize Ye , Xiaoyu Xu , Yunshan Zhong , Jianchao Luo , Zheyan Zhang , Jing Chen , Zhongxi Chen , Jianping Cai , Xiaodan Zhang , Jianchang Qian

Abstract

This study aimed to elucidate the impact of variations in liver enzyme activity, particularly CYP3A4, on the metabolism of furmonertinib. An in vitro enzyme incubation system was established for furmonertinib using liver microsomes and recombinant CYP3A4 baculosomes, with analytes detected by LC-MS/MS. The pharmacokinetic characteristics of furmonertinib were studied in vivo using Sprague-Dawley rats. It was found that telmisartan significantly inhibited the metabolism of furmonertinib, as demonstrated by a significant increase in the AUC of furmonertinib when co-administered with telmisartan, compared to the furmonertinib-alone group. Mechanistically, it was noncompetitive in rat liver microsomes, while it was mixed competitive and noncompetitive in human liver microsomes and CYP3A4. Considering the genetic polymorphism of CYP3A4, the study further investigated its effect on the kinetics of furmonertinib. The results showed that compared to CYP3A4.1, CYP3A4.29 had significantly increased activity in catalyzing furmonertinib, whereas CYP3A4.7, 9, 10, 12, 13, 14, 18, 23, 33, and 34 showed markedly decreased activity. The inhibitory activity of telmisartan varied in CYP3A4.1 and CYP3A4.18, with IC50 values of 8.56 ± 0.90?μM and 27.48 ± 3.52?μM, respectively. The key loci affecting the inhibitory effect were identified as ARG105, ILE301, ALA370, and LEU373. Collectively, these data would provide a reference for the quantitative application of furmonertinib.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Telmisartan 144701-48-4 C33H30N4O2 952 suppliers $5.00-$1250.00
Telmisartan 144701-48-4 C33H30N4O2 952 suppliers $5.00-$1250.00
Telmisartan 144701-48-4 C33H30N4O2 952 suppliers $5.00-$1250.00
Telmisartan 144701-48-4 C33H30N4O2 952 suppliers $5.00-$1250.00
Carvedilol 72956-09-3 C24H26N2O4 652 suppliers $20.00-$700.00
Carvedilol 72956-09-3 C24H26N2O4 652 suppliers $20.00-$700.00
Telmisartan 144701-48-4 - Inquiry
Telmisartan 144701-48-4 - Inquiry

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