Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients.
The objective of this study was to evaluate whether genetic polymorphisms of CYP2C19, CYP3A5 and MDR1 significantly impact the interaction between tacrolimus and rabeprazole or lansoprazole. Seventy-three recipients were randomly assigned after renal transplantation to receive repeated doses of tacrolimus for 28 days with a regimen of either 20 mg of rabeprazole or 30 mg of lansoprazole. Blood concentrations of tacrolimus were measured by microparticle enzyme immunoassay. The mean daily dose and the dose-adjusted area under the plasma concentration-time curves from 0 to 12 h (AUC(0-12)) of tacrolimus coadministered with rabeprazole or lansoprazole were the lowest and highest, respectively, in CYP2C19 poor metabolizers (PMs) having the CYP3A5*3/*3 genotype (0.084 and 0.112 mg/kg/day and 1.269 and 1.033 ng.h/ml/mg/kg, respectively). On the other hand, the mean dose-adjusted AUC(0-12) of tacrolimus coadministered with rabeprazole or lansoprazole were the highest in CYP2C19 PMs having the MDR13435CC+CT genotype, but not significantly. The present study indicates that there are significant interactions between tacrolimus and rabeprazole or lansoprazole in CYP2C19 PM renal transplant recipients bearing the CYP3A5*3/*3 genotypes. For recipients having these genetic polymorphisms, lower dosages of tacrolimus are required to achieve the target therapeutic index.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan. m-miura@hos.akita-u.ac.jp
Inoue
Kazuyuki
K
Kagaya
Hideaki
H
Satoh
Shigeru
S
Tada
Hitoshi
H
Sagae
Yoshinori
Y
Habuchi
Tomonori
T
Suzuki
Toshio
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D064747:Lansoprazole; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic; D064750:Rabeprazole; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D064747:Lansoprazole; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus