Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C(0) )/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C(0) /dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28±26.45, 59.12±24.00, 62.43±41.12, and 57.01±17.34 vs. 112.37± 76.60, 123.21±59.57, 163.34±76.23, and 183.07±107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose-corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01±17.34 vs. 100.09±24.78; P=0.016). Only the ABCB1 TGC (3435-2677-1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR=4.73; CI: 1.3-16.7; P=0.02). Our findings indicate that the CYP3A4*1B-CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.