Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations.
OBJECTIVE
The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes.


METHODS
Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases.


RESULTS
Mean omeprazole AUC (0,infinity) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose.


CONCLUSIONS
This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.
Uno
Tsukasa
T
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan. uno-hki@umin.ac.jp
Niioka
Takenori
T
Hayakari
Makoto
M
Yasui-Furukori
Norio
N
Sugawara
Kazunobu
K
Tateishi
Tomonori
T
D000284:Administration, Oral; D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D007275:Injections, Intravenous; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction
D000897:Anti-Ulcer Agents; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole