title: Enantioselective disposition of lansoprazole and rabeprazole in human plasma.
abstract: Lansoprazole is extensively metabolized by CYP2C19 and CYP3A4 in the liver, whereas rabeprazole is primarily converted non-enzymatically to rabeprazole-thioether, with only some being oxidized by CYP2C19 and CYP3A4. Lansoprazole and rabeprazole possess asymmetric sulfur in their chemical structure and have typically been used clinically as a racemic mixture. This article reviews the pharmacokinetic differences between enantiomers of lansoprazole and rabeprazole in relation to the CYP2C19 genotypes. In our studies in healthy Japanese subjects, the magnitude of contribution of each lansoprazole enantiomer for CYP2C19 was greater than that for CYP3A4. CYP2C19 influenced the disposition of (S)-lansoprazole to a greater extent than the (R)-enantiomer. The R/S ratios for the AUC of lansoprazole in CYP2C19 homEMs, hetEMs and PMs was 12.7, 8.5 and 5.8, respectively. On the other hand, (R)-rabeprazole disposition was influenced to a greater degree by CYP2C19 genetic polymorphisms than (S)-rabeprazole. However, the R/S ratios for the AUC of rabeprazole in CYP2C19 homEMs, hetEMs and PMs was only 1.8, 2.2 and 2.4, respectively, suggesting a lesser effect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole compared to lansoprazole. Such a difference in the AUC between rabeprazole enantiomers is likely to be dependent on stereoselectivity in the CYP3A4-mediated metabolic conversion from rabeprazole-thioether to rabeprazole. Both enantiomers of these PPIs have been reported to possess equal potency. Therefore, particularly with lansoprazole, the use of (R)-lansoprazole alone would be highly desirable for use in clinical applications.
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Alita 010-8543, Japan. m-miura@hos.akita-u.ac.jp
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000502:physiology; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D064748:Dexlansoprazole; D005838:Genotype; D006801:Humans; D064747:Lansoprazole; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000502:physiology; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D013237:Stereoisomerism
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D064748:Dexlansoprazole