Enantioselective disposition of rabeprazole in relation to CYP2C19 genotypes

Abstract

Aim: Rabeprazole is metabolized to some extent by CYP2C19. The purpose of this study was to elucidate the pharmacokinetics of each rabeprazole enantiomer in three different CYP2C19 genotype groups.

Methods: Twenty-four healthy subjects, of whom each each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs) and poor metabolizers (PMs) for CYP2C19, participated in our study. After a single oral dose of 20 mg of racemic rabeprazole, the plasma concentrations of the rabeprazole enantiomers were measured over the course of 24 h.

Results: The area under the plasma concentration-time curves (AUC) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.8-, 2.2- and 2.4-fold, respectively, greater than those of (S)-rabeprazole; the relative AUC ratios of (R)- and (S)-rabeprazole in homEMs, hetEMs and PMs were 1:1.1:2.1 and 1:0.9:1.5, respectively. The mean maximum plasma concentrations (Cmax) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.7-, 1.9- and 1.8-fold higher, respectively, than those of the corresponding (S)-enantiomer (P<0.05). There was no difference between homEMs and PMs in the elimination half-life of (S)-rabeprazole, whereas the elimination half-life of (R)-rabeprazole was significantly longer in PMs than in homEMs [1.7 h (1.4, 2.0) (mean (95% confidence interval)]vs. 0.8 h (0.6, 1.0), respectively, P<0.0001).

Conclusions: (R)-Rabeprazole disposition was influenced to a greater degree by CYP2C19 genetic polymorphisms than was that of (S)-rabeprazole. The effect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole was less than those of lansoprazole and omeprazole.

Figure 1

Mean ± SD plasma concentration–time profiles of (R)-rabeprazole (•) and (S)-rabeprazole (○) for A: homozygous extensive metabolizers (EMs); B: heterozygous EMs; and C: poor metabolizers, after a 20-mg oral dose of racemic rabeprazole