The effect of CYP3A4 genetic polymorphism and drug interaction on the metabolism of istradefylline

Abstract

AimThis study investigated into the effect of CYP3A4 genetic polymorphism on istradefylline metabolism. Moreover, the potential drug-drug interaction with istradefylline was determined as well as underlied mechanism. MethodIn vitro, enzymatic reaction was performed to determine the kinetic parameters of CYP3A4 and its variants on catalyzing istradefylline. Meanwhile, the rat liver microsomes incubation assay was applied to screen interacting drugs. In vivo, SD rats were used to investigate the selected drug interaction. UPLC-MS/MS was used to detect the metabolite M1. ResultThe results demonstrated that the relative clearance rate of CYP3A4.29 decrease significantly compared with CYP3A4.1. But there is no statistically diverse in activities among CYP3A4.1, 2 and 3. The relative clearance rates of the remaining variants are significantly decreased compared with CYP3A4.1. In addition, 148 drugs were screened to determine the potential interaction with istradefylline, among which calcium channel blockers were identified. It's indicated that nimodipine has a significant inhibitory effect on metabolizing istradefylline with IC50 of 6.927 ± 0.372 μM, which via competitive and non-competitive mixed mechanism. In vivo, when istradefylline and nimodipine was co-administered to SD rats, we found the main pharmacokinetic parameters of M1 reduced remarkably, including AUC, MRT, Cmax and CLz/F. ConclusionCYP3A4 genetic polymorphism and nimodipine affect the metabolism of istradefylline. Thus, the present study provided reference data for clinical individualized medicine of istradefylline.