Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients.
To assess the effects of intestinal cytochrome P450 2C19 on the interaction between tacrolimus and proton pump inhibitors, we examined the concentration/dose ratio [(ng/ml)/(mg/day)] of tacrolimus coadministered with omeprazole (20 mg) or lansoprazole (30 mg) to 89 adult living-donor liver transplant patients on postoperative days 22 to 28, considering the CYP2C19 genotypes of the native intestine and the graft liver, separately. The concentration/dose ratio of tacrolimus coadministered with omeprazole was significantly higher in patients with two variants (*2 or *3) for intestinal CYP2C19 (median, 6.38; range, 1.55-22.9) than intestinal wild-type homozygotes (median, 2.11; range, 1.04-2.54) and heterozygotes (median, 2.11; range, 0.52-4.33) (P = 0.010), but the extent of the increase was attenuated by carrying the wild-type allele in the graft liver even when patients were CYP3A5*1 noncarriers. Conversely, the CYP2C19 polymorphisms both in the native intestine and in the graft liver little influenced the interaction between tacrolimus and lansoprazole, but CYP3A5*1 noncarriers showed higher tacrolimus concentration/dose ratio than CYP3A5*1 carriers. Furthermore, our experiments in vitro revealed that lansoprazole had a stronger inhibitory effect on the CYP3A5-mediated metabolism of tacrolimus than omeprazole, although not significantly (IC(50) = 19.9 +/- 13.8 microM for lansoprazole, 53.7 +/- 6.1 microM for omeprazole). Our findings suggest that intestinal and graft liver CYP2C19 plays a relatively greater role in the metabolism of omeprazole than it does for lansoprazole, so that the effects of CYP3A5 on the metabolism of tacrolimus might be masked by the interaction with omeprazole associated with the CYP2C19 genotype.
Hosohata
Keiko
K
Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
Masuda
Satohiro
S
Katsura
Toshiya
T
Takada
Yasutsugu
Y
Kaido
Toshimi
T
Ogura
Yasuhiro
Y
Oike
Fumitaka
F
Egawa
Hiroto
H
Uemoto
Shinji
S
Inui
Ken-ichi
K
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064747:Lansoprazole; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology* / Q000627:therapeutic use; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D007166:Immunosuppressive Agents; D064747:Lansoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D016559:Tacrolimus