Formation of omeprazole sulphone but not 5-hydroxyomeprazole is inhibited by grapefruit juice.
OBJECTIVE
To determine the effect of grapefruit juice on omeprazole metabolism in vivo.


METHODS
This was a randomized crossover study with a 2 week washout period. Omeprazole (20 mg) was taken orally by 13 healthy volunteers after an overnight fast with either grapefruit juice or water. Serial blood samples were obtained over 12 h and standardized meals were served 3 and 10 h after the administration of omeprazole. Plasma concentrations of omeprazole and its major metabolites, 5-hydroxyomeprazole and omeprazole sulphone, were determined by high performance liquid chromatography (h.p.l.c.).


RESULTS
Mean area under the plasma concentration vs time curve (AUC) between 0 and 12 h for omeprazole sulphone was approximately 20% lower (P<0.01) in the group receiving grapefruit juice. There was no significant difference in the mean AUC of 5-hydroxyomeprazole or omeprazole. The AUC ratio of omeprazole sulphone to omeprazole, an index of CYP3A4 activity, was decreased by 33% (P<0.001) after administration of grapefruit juice whereas the AUC ratio of 5-hydroxyomeprazole to omeprazole, an index of CYP2C19 activity, did not differ between the two phases of the study. Although the time to peak concentration (tmax ) and terminal half-life (t1/2,z) of omeprazole and its two main metabolites were not altered, the peak concentration (Cmax ) of omeprazole sulphone was significantly reduced after administration of grapefruit juice.


CONCLUSIONS
Administration of grapefruit juice decreased the formation of omeprazole sulphone but not 5-hydroxyomeprazole. These results indicate that activities of CYP3A4, but not of CYP2C19, are inhibited by the simultaneous administration of grapefruit juice.
Tassaneeyakul
W
W
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Vannaprasaht
S
S
Yamazoe
Y
Y
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001628:Beverages; D002957:Citrus; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; C040450:omeprazole sulfone; D003577:Cytochrome P-450 Enzyme System; C049963:5-hydroxymethylomeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole