Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH.
BACKGROUND
Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status.


OBJECTIVE
To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes.


METHODS
Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post-dose days 1 and 8, 24-h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined.


RESULTS
After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed.


CONCLUSIONS
The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.
Shirai
N
N
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. naohito@hama-med.ac.jp
Furuta
T
T
Moriyama
Y
Y
Okochi
H
H
Kobayashi
K
K
Takashima
M
M
Xiao
F
F
Kosuge
K
K
Nakagawa
K
K
Hanai
H
H
Chiba
K
K
Ohashi
K
K
Ishizaki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000897:Anti-Ulcer Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D005745:Gastric Acidity Determination; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009853:Omeprazole / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D064750:Rabeprazole
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D006180:Proton-Translocating ATPases; D009853:Omeprazole