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.

Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation

“…This result is consistent with the several reports suggesting that significant interactions between TAC and LAN occurred in patients with genetic defects of CYP2C19. 21,23,24 In our study, there were 12 HSCT recipients receiving FLCZ instead of VRCZ. The TAC C/D ratio has been reported to have increased more than 4.5-fold after the switch from FLCZ to VRCZ in HSCT recipients with orally administered TAC.…”

Proton Pump Inhibitor Co-medication Reduces Mycophenolate Acid Drug Exposure in Heart Transplant Recipients

“…However, little is known about the interaction between PPI and MMF. 8,11,12 Indeed, to date no other publications have described MMF-PPI pharmacokinetics in heart transplant recipients. This study was neither aimed nor powered to demonstrate MMF absorption.…”

Absence of Influence of Concomitant Administration of Rabeprazole on the Pharmacokinetics of Tacrolimus in Adult Living-donor Liver Transplant Patients: A Case–control Study

“…4,5) Because CYP2C19 and CYP3A4/5 are mainly responsible for the metabolism of PPIs, 6) PPIs themselves inhibit the metabolism of tacrolimus via CYP3A4/5 in patients carrying variant alleles of CYP2C19, thereby increasing blood concentrations of tacrolimus in renal transplant patients. [7][8][9] Recently, we reported increased trough tacrolimus concentrations in association with the CYP2C19 defect genotype in living-donor liver transplant (LDLT) patients receiving omeprazole and with the CYP3A5 defect genotype in patients receiving lansoprazole. 10) Rabeprazole is less affected by CYP2C19 and CYP3A4s than omeprazole or lansprazole.…”