Effect Of CYP2C19Polymorphism On Pharmacokinetics Of Rabeprazole Sodium In Human

Objectives:This research was designed to evaluate the influence of CYP2C19polymorphism on the pharmacokinetics of rabeprazole sodium after single dose of rabeprazole enteric coated tablet or rabeprazole orally disintegrating tablet(ODT) at20mg.Methods:First, a method needs to be developed to detect the concentration of rabeprazole sodium in human plasma, and an improved HPLC method was established according to the HPLC、HPLC-MS、HPLC-MS/MS methods reported, considering rabeprazole is sensitive to acid, light and heat. Second, a randomized crosse-over clinical research was conducted on24subjects, a single dose of20mg rabeprazole enteric coated tablet or rabeprazole orally disintegrating tablet was administrated, blood samples were collected at different time points, then the plasma concentration of rabeprazole sodium was detected. Third, subjects were genotyped for CYP2C19*2, CYP2C19*3, CYP2C19*17alleles by direct sequencing, and were assigned to different phenotype groups. Finally, pharmacokinetic parameters of two tablets between different groups were statistically analyzed, respectively, using data collected above.Results:First, a linear range of10-2000μg·L-1(r2=0.998) was established, with LLOQ of10μg-L-1; for the low, middle, high level concentration, the extraction recovery were (80.58±7.52)%,(86.96±2.31)%,(92.24±2.41)%, respectively; within-batch precision were2.76%～10.92%,2.42%～4.34%,1.91%～2.38%, and between-batch precision were9.91%,3.77%,3.20%; the accuracy were (102.8518.14)%,(99.68±2.41)%,(100.92±2.07)%. Second,21records of plasma concentration were included in the statistical analysis, as21of23subjects completed the research, results of genotyping and distribution were CYP2C19*1/*1(homEMs, n=7), CYP2C19*1/*2(hetEMs, n=11), CYP2C19*2/*2(PMs, n=3), no CYP2C19*17mutation was found. Finally, the comparison of means of the pharmacokinetic parameters indicated that there was no difference with Tmax among homEMs, hetEMs and PMs. However, for orally disintegrating tablet, Cmax was identical, in contrast, AUC0-t was different among three groups, t1/2was different in homEMs VS PMs, and hetEMs VS PMs, AUC0-∞was different in homEMs VS PMs; for enteric coated tablet, AUC0-t, AUC0-∞differed significantly in homEMs VS hetEMs, and homEMs VS PMs, Cmax was different in homEMs VS hetEMs, t1/2was different among three groups.Conclusions:The HPLC method was specific, accurate and rapid, which is suitable for pharmacokinetic study. CYP2C19polymorphism had an effect on the pharmacokinetic parameters of AUC, Cmax and t1/2, while the influence differ between two kinds of tablets.