Enantioselective disposition of rabeprazole in relation to CYP2C19 genotypes.
OBJECTIVE
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.
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Masatomo
M
Miura
Hideaki
H
Kagaya
Hitoshi
H
Tada
Tsukasa
T
Uno
Norio
N
Yasui-Furukori
Tomonori
T
Tateishi
Toshio
T
Suzuki
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D064750:Rabeprazole
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D064750:Rabeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole