Effect of clarithromycin on the enantioselective disposition of lansoprazole in relation to CYP2C19 genotypes.
The aim of this study was to examine the effect of clarithromycin, a CYP3A4 inhibitor, on the enantioselective disposition of lansoprazole among three different CYP2C19 genotype groups in healthy Japanese subjects. These subjects included 6 each of homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), and poor metabolizers (PMs). In the EMs of CYP2C19, clarithromycin markedly increased Cmax and the AUC0-infinity of (S)-lansoprazole and (S)-hydroxylansoprazole compared with those of the corresponding (R)-enantiomers. Clarithromycin significantly increased Cmax and the AUC0-infinity of (S)-lansoprazole in the homEMs by 110% and 115%, respectively, and in the hetEMs by 105% and 103%, respectively, compared with placebo. Furthermore, clarithromycin slightly prolonged the elimination half-life of (R)-lansoprazole in the homEMs and hetEMs but did not alter that of (S)-lansoprazole. In the of PMs CYP2C19, clarithromycin significantly increased Cmax and the AUC0-infinity and significantly prolonged the elimination half-lives of (R)- and (S)-lansoprazole by 51% and 49%, respectively. The present study suggests that there are significant drug interactions between (R)- or (S)-lansoprazole and clarithromycin in EMs by inhibiting the CYP3A4-catalyzed sulfoxidation primarily during the first pass, whereas in PMs, the overall metabolism of lansoprazole is inhibited.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Tada
Hitoshi
H
Yasui-Furukori
Norio
N
Uno
Tsukasa
T
Sugawara
Kazunobu
K
Tateishi
Tomonori
T
Suzuki
Toshio
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D017291:Clarithromycin / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D064748:Dexlansoprazole; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D064747:Lansoprazole; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D054328:Proton Pump Inhibitors; D013237:Stereoisomerism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; 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; D017291:Clarithromycin; D009853:Omeprazole; D064748:Dexlansoprazole