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Functional characterization of 27 CYP3A4 protein variants to metabolize regorafenib in vitro

Ying-Hui Li1, Qian-Meng Lin1, Ni-Hong Pang1

  • 1Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, China.

Basic & Clinical Pharmacology & Toxicology
|May 7, 2019
PubMed
Abstract

Insights

This study characterized 27 CYP3A4 variants’ impact on regorafenib metabolism. Four variants showed increased activity, one showed none, and others had decreased or similar activity compared to wild-type CYP3A4.1.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Enzyme Kinetics

Background:

  • Regorafenib, a tyrosine kinase inhibitor, is primarily metabolized by CYP3A4.
  • Genetic variations in CYP3A4 can significantly alter regorafenib metabolism.
  • Understanding these variations is crucial for personalized medicine and optimizing regorafenib therapy.

Purpose of the Study:

  • To investigate the in vitro catalytic characteristics of 27 novel CYP3A4 protein variants on the oxidative metabolism of regorafenib.
  • To determine how genetic polymorphisms in CYP3A4 affect regorafenib clearance.
  • To provide foundational data for clinical studies on regorafenib pharmacogenetics.

Main Methods:

  • Incubation of wild-type CYP3A4.1 and 27 variants with varying concentrations of regorafenib (0.5–20 μmol/L) for 30 minutes.
  • Detection and quantification of regorafenib-N-oxide, a key metabolite, using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
  • Determination of intrinsic clearance values for each CYP3A4 variant.

Main Results:

  • CYP3A4.20 exhibited no detectable enzyme activity.
  • Five variants (CYP3A4.5, .16, .19, .24, .29) showed clearance values comparable to wild-type CYP3A4.1.
  • Four variants (CYP3A4.14, .15, .28, .31) demonstrated significantly increased enzymatic activity, while the remaining variants displayed markedly decreased intrinsic clearance.

Conclusions:

  • This study provides the first comprehensive in vitro functional characterization of 27 CYP3A4 variants concerning regorafenib metabolism.
  • The identified variants exhibit diverse catalytic activities, impacting regorafenib clearance.
  • These findings may inform future clinical research and guide personalized regorafenib treatment strategies.
Keywords:
CYP3A4genetic polymorphismmetabolismregorafenibregorafenib-N-oxide

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