Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4'-hydroxylation phenotype and genotype.
OBJECTIVE
To assess the possible relationship between the metabolic disposition of pantoprazole and genetically determined S-mephenytoin 4'-hydroxylation phenotype and genotype.


METHODS
The pharmacokinetic disposition of pantoprazole was investigated in 14 Japanese male volunteers (seven extensive and seven poor metabolizers of S-mephenytoin). All subjects received a single 40 mg oral dose of pantoprazole as the enteric-coated formulation.


RESULTS
An interphenotypic difference in the metabolic disposition of pantoprazole was observed: the mean values for area under the concentration-time curve (AUC), elimination half-life (t1/2), and apparent oral clearance were significantly (p < 0.01) greater, longer, and lower, respectively, in the poor metabolizers than in the extensive metabolizers. The mean AUC of pantoprazole sulfone was greater (p < 0.01) in the poor metabolizers than in the extensive metabolizers, whereas the mean AUC of the main demethylated metabolite (M2) was lower (p < 0.01) in the poor metabolizers than in the extensive metabolizers. A significant negative correlation was observed between the individual values for log10% urinary excretion of 4'-hydroxymephenytoin and AUC of pantoprazole (rs = -0.816; p < 0.005). The CYP2C19 genotyping test results were found to be in a complete accordance with the phenotypes.


CONCLUSIONS
These data indicated that the metabolic disposition of pantoprazole is under the pharmacogenetic control of S-mephenytoin 4'-hydroxylase (CYP2C19).
Tanaka
M
M
Drug Metabolism and Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.
Ohkubo
T
T
Otani
K
K
Suzuki
A
A
Kaneko
S
S
Sugawara
K
K
Ryokawa
Y
Y
Hakusui
H
H
Yamamori
S
S
Ishizaki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007564:Japan; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000652:urine; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors; D013454:Sulfoxides / Q000493:pharmacokinetics* / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; C025687:4-hydroxymephenytoin; D003577:Cytochrome P-450 Enzyme System; D000077402:Pantoprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin