Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

P>What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC(0-12)) and maximum plasma concentration (C-max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45 center dot 2 +/- 20 center dot 0 vs. 71 center dot 0 +/- 34 center dot 1 ng center dot h/mL/mg, P < 0 center dot 0001 and 6 center dot 3 +/- 2 center dot 6 vs. 9 center dot 3 +/- 7 center dot 0 ng/mL/mg, P = 0 center dot 0017, respectively) and between co-administration with and without lansoprazole (74 center dot 5 +/- 34 center dot 0 vs. 52 center dot 4 +/- 27 center dot 4 ng center dot h/mL/mg, P = 0 center dot 0054 and 10 center dot 9 +/- 8 center dot 8 vs. 6 center dot 7 +/- 3 center dot 0 ng/mL/mg, P = 0 center dot 0024, respectively). In a multiple regression analysis, the dose-adjusted AUC(0-12) and C-max of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.