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Updated: Jan 25, 2026

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
In-vitro and in-vivo CYP3A4 Variants: Neratinib metabolism and drug interaction risk
Zheyan Zhang1, Xiaoyu Huang2, Chen Gan2
1Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
To investigate the effects of metabolic enzyme activity inhibition and genetic polymorphisms on the pharmacokinetics and pharmacodynamics of neratinib, we employed a combined approach of molecular docking and an in-vitro enzymatic reaction system to identify potential inhibitors in this study. The levels of neratinib and its metabolite were quantified using ultra performance liquid chromatography with tandem mass spectrometry. Additionally, in-vivo studies were conducted using Female Sprague-Dawley rats, and subsequent metabolic enzyme kinetics analyses were performed to evaluate the impact of genetic polymorphisms on neratinib metabolism. Among the 10 drugs screened, the antihistamine loratadine showed a pronounced inhibitory effect on neratinib metabolism in vitro, with a relative inhibition rate of 94.3 %, significantly increasing the systemic exposure of neratinib in rats. This finding is attributed to the mixed-type inhibition of liver microsome activity by loratadine. Furthermore, the differential inhibitory effects of loratadine toward CYP3A4.1 and CYP3A4.34 underscore the role of CYP3A4 genetic polymorphisms in modulating the inhibitory potency of loratadine toward neratinib. In conclusion, our study suggests that coadministration of loratadine and genetic polymorphisms in CYP3A4 can significantly influence neratinib metabolism, necessitating caution regarding potential drug-drug interactions in clinical settings.
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