Genetic polymorphisms of the CΥP3A4, CΥP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus

Abstract

Background: The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1. Objective: Our objective was to determine the role of genetic polymorphisms in CΥP3A4, CΥP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics. Methods: Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CΥP3A4*1B and *3, CΥP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype. Results: Tacrolimus dose-adjusted trough levels were higher in CΥP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/ kg (P