The relationship between CYP2C9 gene polymorphisms and azilsartan metabolism in vitro.

Background: 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.

Research designand methods: 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.

Results: 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.

Conclusion: 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.