ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1643618
Impact of Metabolic Enzyme Activity Variability on Dabrafenib Disposition
Provisionally accepted
- 1Wenzhou Medical University, Wenzhou, China
- 2The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- 3Wenzhou Seventh People’s Hospital, Wenzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
This study evaluated the impact of metabolic enzyme activity variations on dabrafenib disposition. An optimized liver microsomal incubation system was employed to screen for inhibitors of dabrafenib metabolism, complemented by in vivo experiments in Sprague-Dawley rats. Analyte were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Loratadine was identified as the most potent inhibitor, exhibiting an IC50 of 14.01 ± 2.82 µM in rat liver microsomes versus 52.40 ± 4.63 µM in human liver microsomes. It suppressed > 90% of dabrafenib metabolism via mixed-type inhibition. In vivo co-administration of loratadine significantly increased systemic exposure to dabrafenib compared to dabrafenib alone. Specifically, the half-life (T1/2) and peak concentration (Cmax) increased by 548.65% and 237.43%, respectively, while CLz/F and Vz/F markedly decreased . These effects were attributed to loratadine-mediated inhibition. Additionally, CYP3A4 genetic polymorphisms substantially influenced dabrafenib pharmacokinetics: the CYP3A4.28 variant demonstrated higher intrinsic clearance than the wild-type CYP3A4.1, whereas CYP3A4.8 showed reduced clearance. Collectively, both loratadine-mediated drug-drug interactions and CYP3A4 genetic variations critically alter dabrafenib metabolism, necessitating dosage adjustments when these factors coexist.
Keywords: CYP3A4, dabrafenib, Loratadine, Drug-Drug Interaction, Genetic polymorphism
Received: 09 Jun 2025; Accepted: 12 Aug 2025.
Copyright: © 2025 Wang, Chen, Chen, Chen, Yuan, Dai, Chen and Zhang. 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: Xiaodan Zhang, Wenzhou Seventh People’s Hospital, Wenzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.