Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes.
Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers--of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19--received three 6-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60-mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC(0-infinity) of lansoprazole by 3.8-fold (P < .01) in homozygous EMs and by 2.5-fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine-mediated percentage increase in the AUC(0-infinity) of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.
Yasui-Furukori
Norio
N
Department of Clinical Pharmacology, Hirosaki University, School of Medicine, Hirosaki 036-8562, Japan.
Saito
Masato
M
Uno
Tsukasa
T
Takahata
Takenori
T
Sugawara
Kazunobu
K
Tateishi
Tomonori
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000897:Anti-Ulcer Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D064747:Lansoprazole; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D016666:Fluvoxamine; D064747:Lansoprazole; D006899:Mixed Function Oxygenases; D009853:Omeprazole; D054328:Proton Pump Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; C581535:Lansoprazole Sulfone; C045793:CYP2C19 protein, human