title: Enantioselective disposition of lansoprazole in relation to CYP2C19 genotypes in the presence of fluvoxamine.
abstract: OBJECTIVE
  Lansoprazole is affected by polymorphism of CYP2C19. The aim of this study was to examine the effects of fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetics of each lansoprazole enantiomer among three different CYP2C19 genotype groups.
  
  
  METHODS
  Eighteen healthy subjects, of whom six each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), or poor metabolizers (PMs) for CYP2C19, participated in the study. Each subject received either placebo or fluvoxamine, 25 mg twice daily for 6 days, then a single oral dose of 60 mg of racemic lansoprazole. The plasma concentrations of lansoprazole enantiomers and lansoprazole sulphone were subsequently measured for 24 h post lansoprazole administration using liquid chromatography.
  
  
  RESULTS
  In the homEMs and hetEMs, fluvoxamine significantly increased the AUC(0, infinity) and C(max) and prolonged the elimination half-life of both (R)- and (S)-lansoprazole, whereas in the PMs, the only statistically significant effect of fluvoxamine was on the AUC(0, infinity) for (R)-lansoprazole. The mean fluvoxamine-mediated percent increase in the AUC(0, infinity) of (R)-lansoprazole in the homEMs compared with the PMs was significant (P = 0.0117); however, C(max) did not differ among the three CYP2C19 genotypes. On the other hand, fluvoxamine induced a significant percent increase in both the AUC(0, infinity) and C(max) for (S)-lansoprazole in the homEMs compared with the hetEMs (P = 0.0007 and P = 0.0125, respectively) as well as compared with the PMs (P < 0.0001 for each parameter). The mean R : S ratio for AUC(0, infinity) of lansoprazole in the homEMs was significantly different between the placebo and the fluvoxamine treatment groups (12.7 (9.1, 16.8) vs 6.4 (5.4, 7.4), respectively, P < 0.0001), though not in the PMs (5.5 (4.3, 6.7) vs 5.9 (5.3, 6.5), respectively).
  
  
  CONCLUSIONS
  The magnitude of the contribution of CYP2C19 to the metabolism of (S)-lansoprazole is much greater compared with that of the (R)-enantiomer. In extensive metabolizers, hepatic CYP2C19 plays an important role in the absorption and elimination of lansoprazole, particularly the (S)-enantiomer.
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tada
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Uno
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Sugawara
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
authors.forename: Toshio
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D064748:Dexlansoprazole; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D064747:Lansoprazole; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; D064747:Lansoprazole; C581535:Lansoprazole Sulfone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D016666:Fluvoxamine; D064748:Dexlansoprazole