The effect of gene polymorphism on ticagrelor metabolism: an study of 22 CYP3A4 variants in Chinese Han population.

BACKGROUND

Ticagrelor is a novel oral antiplatelet agent which can selectively inhibit P2Y12 receptor. Bleeding and dyspnea are common adverse reactions of ticagrelor in clinic. The side effects of ticagrelor are correlated with the plasma concentration of ticagrelor.

OBJECTIVE

This study aimed to evaluate the catalytic characteristics of 22 CYP3A4 alleles identified in the Chinese Han population on the metabolism of ticagrelor , focusing on the effect of CYP3A4 polymorphism on ticagrelor metabolism.

METHODS

In this study, insect cells were used to express 22 CYP3A4 variants, which were then incubated with 1-50 µM ticagrelor at 37 °C for 30 minutes to obtain the metabolite (AR-C124910XX). AR-C124910XX was detected by UHPLC-MS/MS to calculate the kinetic parameters, including Km, Vmax and CLint.

RESULTS

Compared to the wild-type, most CYP3A4 alleles exhibited significant differences in intrinsic clearance. The intrinsic clearance of CYP3A4*11, *18 and 33 was much higher than that of wild-type; four variants exhibited similar intrinsic clearance values as the wild-type enzyme; The remaining 14 variants showed significantly reduced intrinsic clearance values, ranging from 1.48% to 75.11% of the wild-type; CYP3A430 displayed weak or no activity.

CONCLUSION

This study conducted a comprehensive assessment of the effect of CYP3A4 variants on ticagrelor's metabolism. The results suggested that there is allele-specific activity towards ticagrelor . These findings can provide some insights and predictions for treatment strategies and risk assessments associated with ticagrelor in clinical practice.