Effect of 36 CYP2C9 variants found in the Chinese population on losartan metabolism in vitro

Abstract

1. CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Among these variants, we recently identified 21 novel alleles (*36–*56) in the Han Chinese population. The aim of this study was to assess the catalytic activities of 36 CYP2C9 variants found in the Chinese population toward losartan in vitro.

2. Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.5–25 μM losartan for 30 min at 37 °C. Next, the products were extracted, and signal detection was performed using high-performance liquid chromatography.

3. Compared with wild-type CYP2C9.1, the intrinsic clearance (V_max/K_m) values of all variants except for CYP2C9.56 were significantly altered. One variant exhibited markedly increased values (>250%), whereas 33 variants exhibited significantly decreased values (from 20 to 96%) due to increased K_m and/or decreased V_max values.

4. These findings suggest that more attention should be paid to subjects carrying these infrequent CYP2C9 alleles when administering losartan in the clinic.

• Allelic variant
• catalytic activity
• CYP2C9
• losartan

Acknowledgements

We are grateful to the members of the Beijing Institute of Geriatrics of the Ministry of Health for their advice and assistance.