Different contribution of CYP2C19 in the in vitro metabolism of three proton pump inhibitors.
A series of clinical studies on the cytochrome P450 2C19 (CYP2C19) genotype and the pharmacokinetics and pharmacodynamics of three proton pump inhibitors (PPIs), omeprazole, lansoprazole and rabeprazole, have been conducted to establish the individualized pharmacotherapy based on the CYP2C19 genotyping, and in the present study, the CYP2C19 genotype-dependency was more pronounced for omeprazole than the other two. Herein, to validate further the difference among 3 PPIs in CYP2C19 genotype-dependency on the phenotype, a comparative in vitro study was conducted using the human liver microsomes and newly developed anti-human CYP antibodies. The residual concentrations of omeprazole and lansoprazole in 5 lots of human liver microsomes were dependent on the CYP2C19 activities, however, for rabeprazole, there was no correlation. The hydroxylation of omeprazole was more inhibited by anti-CYP2C19 antibody than lansoprazole, whereas anti-CYP3A4 antibody showed similar inhibition. In conclusion, the relative contribution of CYP2C19 on total metabolism of 3 PPIs elucidated herein coincided with the CYP2C19 genotype-dependent pharmacokinetics.
Kita
Tomoko
T
Department of Hospital Pharmacy, School of Medicine, Kobe University, Chuo-ku, Japan.
Sakaeda
Toshiyuki
T
Baba
Takahiko
T
Aoyama
Nobuo
N
Kakumoto
Mikio
M
Kurimoto
Yoshie
Y
Kawahara
Yuko
Y
Okamura
Noboru
N
Kirita
Shirou
S
Kasuga
Masato
M
Okumura
Katsuhiko
K
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000704:Analysis of Variance; D000906:Antibodies / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000276:immunology / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D064747:Lansoprazole; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000276:immunology / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000378:metabolism*; D054328:Proton Pump Inhibitors; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D064750:Rabeprazole
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000906:Antibodies; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; 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; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006180:Proton-Translocating ATPases; D009853:Omeprazole