Impact of metabolic enzyme activity variability on dabrafenib disposition.

ABSTRACT:

Introduction

The systemic exposure of dabrafenib correlates with its adverse drug reactions. A thorough understanding of its pharmacokinetic profile is crucial for precise clinical application.

Methods

An optimized liver microsomal incubation system was established to screen for inhibitors of dabrafenib metabolism. Recombinant human CYP3A4 microsomes were prepared using a baculovirus-insect cell expression system. Analytes were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The in vivo relevance of the inhibitory effects was further validated in Sprague-Dawley rats.

Results

Loratadine was identified as the most potent inhibitor, with IC₅₀ values of 14.01 ± 2.82 μM in rat liver microsomes and 52.40 ± 4.63 μM i

SUBMITTER: Wang SY 

PROVIDER: S-EPMC12460146 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature