title: Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients.
abstract: 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.
authors: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan. m-miura@hos.akita-u.ac.jp
authors: Masatomo
authors: M
authors: Miura
authors: Kazuyuki
authors: K
authors: Inoue
authors: Hideaki
authors: H
authors: Kagaya
authors: Shigeru
authors: S
authors: Satoh
authors: Hitoshi
authors: H
authors: Tada
authors: Yoshinori
authors: Y
authors: Sagae
authors: Tomonori
authors: T
authors: Habuchi
authors: Toshio
authors: T
authors: Suzuki
mesh_terms: 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*
chemical_list: 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