Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status.
OBJECTIVE
Rabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes.


METHODS
A two-way randomized double-blind, placebo-controlled crossover study was performed. Twenty-one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing.


RESULTS
During placebo administration, the mean AUCs(0,infinity) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml-1h , 1214 (975, 1453) ng ml-1 h and 2762 (2482, 3042) ng ml-1 h (P<0.001), respectively. Fluvoxamine treatment increased AUC(0,infinity) of rabeprazole and rabeprazole thioether by 2.8-fold (P<0.001) and 5.1-fold (P<0.01) in homozygous EMs, and by 1.7-fold (P<0.01) and 2.6-fold (P<0.01) in heterozygous EMs, and significantly prolonged the elimination half-life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine-mediated percentage increase in AUC(0,infinity) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes.


CONCLUSIONS
The present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs.
Uno
Tsukasa
T
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Japan. uno-hki@umin.ac.jp
Shimizu
Mikiko
M
Yasui-Furukori
Norio
N
Sugawara
Kazunobu
K
Tateishi
Tomonori
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001562:Benzimidazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D016666:Fluvoxamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D064750:Rabeprazole; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors; D016666:Fluvoxamine; D006899:Mixed Function Oxygenases; D009853:Omeprazole; D064750:Rabeprazole; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human