# Effect of Cytochrome P450 2C9 genetic polymorphism on agomelatine metabolism in vitro

## TL;DR

This study examines how genetic variations in CYP2C9 affect the metabolism of the drug agomelatine, highlighting implications for personalized medicine.

## Contribution

The study evaluates 37 CYP2C9 variants and their specific effects on agomelatine metabolism, providing new insights into drug metabolism variability.

## Key findings

- Four CYP2C9 variants showed no significant difference in enzyme activity compared to the wild-type CYP2C9*1.
- Eleven variants had significantly higher intrinsic clearance values, while thirteen had significantly reduced values.
- Eight variants displayed complex metabolic patterns, affecting metabolite production unevenly.

## Abstract

Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which potentially lead to adverse effects and therapeutic failure. The aim of this study was to investigate the genetic polymorphism of 37 CYP2C9 alleles and evaluate their catalytic activities in agomelatine metabolism in vitro.

Insect microsomes expressing the 37 recombinant CYP2C9 variants were incubated in a 37 °C water bath with agomelatine. The main active metabolites of agomelatine were detected using a UPLC-MS/MS system. Then, the enzyme kinetic parameters of the 36 variants were calculated and compared with those of the wild-type CYP2C9*1.

Relative to CYP2C9*1, four variants exhibited no significant difference in enzyme activity. Eleven variants exhibited significantly higher intrinsic clearance values, while 13 variants exhibited significantly reduced intrinsic clearance values. The remaining eight variants demonstrated complex metabolic patterns; these variants do not produce the two metabolites equally, and they inhibited the appearance of one metabolite but promoted the production of another metabolite. These results suggest that special attention should be given to subjects carrying poor metabolizers of CYP2C9 alleles when prescribing agomelatine in clinical practice. This study can provide valuable insights for personalized medicine and reduce adverse reactions to some extent.