The relationship between CYP2C9 gene polymorphisms and azilsartan metabolism in vitro

The gene polymorphisms of the CYP2C9, as well as the substrate specificity of the enzyme, result in different clearances for different substrates by CYP2C9 variants.

The CYP2C9 wild type and 38 CYP2C9 variants, expressed in insectmicrosomes, were incubated with azilsartan. The resulting metabolite,O-desethyl azilsartan, was determined by HPLC-MS/MS. The enzyme kineticparameters of the 38 variants were calculated and compared with the wild type.Subsequently, we selected CYP2C9*1, *2, and  *3 as target proteins for molecular docking with azilsartan to elucidate the mechanisms underlying changes in enzyme function.

Compared with CYP2C9*1, three variants (CYP2C9*29, *39, and *49) exhibited markedlyincreased CL_int values (from 170%-275%, *p < 0.05), whereas 28 variants exhibited significantly decreased CL_int values (from 3-63%,*p < 0.05). The molecular docking results showed that the binding energy of CYP2C9*2 and *3 was lower than that of the wild type.

Thisassessment revealed the effect of CYP2C9 gene polymorphisms on azilsartan metabolism, establishing a theoretical basis for further in-vivo studies and clinical applications. This study will help expand the database of CYP2C9 gene-drug pairs and identify appropriate treatment strategies for azilsartan, contributing to the field of precision medicine.