Effect of the New Functional CYP3A4*22, CYP3A5 and ABCB1 Polymorphisms On the Tacrolimus Concentrations in Hispanic Kidney Transplant Recipients.

Abstract

Background: Tacrolimus is a substrate of metabolic enzyme cytochrome P450 3A, and a cell membrane transporter, ABCB1 gene product, P-glycoprotein (P-gp). This study aims to investigate the effect of the new functional CYP3A4*22, CYP3A5 and ABCB1 polymorphisms on Tac trough concentrations in renal transplant recipients (RTRs). Methods: We investigated the impact of the CYP3A4*22 (intron 6 C>T), CYP3A5*3 6986 G>A, ABCB1 C1236>T and ABCB1 C3435>T polymorphisms on Tac pharmacokinetics in 229 Hispanic RTRs at months 1, 3, and 6 post transplantation. Trough blood levels ([Tac](0) in ng/ml), dose-adjusted [Tac](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4*22, CYP3A5 and ABCB1. Results: Frequencies of variant alleles among the RTRs were CYP3A5*3, 82.3%; ABCB1 1236T, 54% and ABCB1 3435T, 56.2%. The CYP3A4*22 variant allele was observed in only 17 (6.6%) patients. The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 29% lower for carriers of the CYP3A4*22 T variant allele than for CC patients (95%CI, -43% to 18%; p=0.02). When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.4- and 3.9-fold higher for Tac than the intermediate metabolizer and extensive metabolizer groups, respectively. Renal function, assessed by calculation of SCr (mg/dL) was not statistically significant between CYP3A4*22 T allele carriers at 1,3,6 months of follow-up compared with wild-type patients. Higher Tac trough blood concentrations were observed in the homozygous CYP3A5*3 allele and homozygous ABCB1 C1236>T TT genotype. Conclusions: The CYP3A4*22 (intron 6 C>T) polymorphism is associated with a significant alter Tac metabolism. Analysis of CYP3A4*22 intron 6 C>T along with CYP3A5*3 and ABCB1 just before transplantation may help to identifying patients at risk of Tac overexposure.