Effect of ABCB1 (3435CT) and CYP3A5 (6986AG) genes polymorphism on tacrolimus concentrations and dosage requirements in liver transplant patients

摘要

Background Tacrolimus (TAC) is an immunosuppressant used in organ transplant recipients. It is a substrate of drug transporter ABCB1 as well as of cytochrome P4503A (CYP3A). Aim To assess the influence of ABCB1 (3435 CT) and CYP3A5 (6986 AG) genes polymorphism of liver transplant donors and recipients on blood level and dose requirements of oral tacrolimus, to help in designing an individualized tacrolimus regimen for liver transplant recipients. Subjects and methods Forty-eight adult liver transplant recipients and their matching living donors were prospectively enrolled in this study. TAC doses and blood concentration were recorded on 1st, 2nd and 3rd days, after 1 and 2 weeks, and at 1, 3 and 6 months postoperatively using ultra performance liquid chromatography Tandem mass spectrometry. Genotyping of ABCB1 (3435CT) and CYP450 3A5 (6986AG) genes were determined by Polymerase chain reaction followed by restriction fragment length polymorphism and by TaqMan allelic discrimination assay techniques, respectively. Results Of the enrolled 48 recipients, CYP3A5 ? 3/ ? 3 and CYP3A5 ? 1/ ? 3 genotypes were detected in 18 (37.5%) and in 20 (41.7%) recipients respectively, while ABCB1 CT and TT genotypes were detected in16 (33.3%) and 10 (20.8%) recipients respectively. TAC daily dose was significantly increased among recipients carrying ABCB1 CC genotype compared to recipients carrying CT and TT genotypes during and after the first month postoperatively. During 1st, 2nd days and 2 weeks post-transplant, a significant increase of TAC concentration / dose ratio was observed among recipients carrying CYP3A5 ? 3 ? 3 genotype than recipients carrying 1 ? 1 ? and 1 ? 3 ? genotypes, and among recipients carrying ABCB1 CT and TT genotypes compared to those carrying CC genotype on 1st, 3rd days and at 3 months postoperatively. Conclusions ABCB1 and CYP3A5 genetic polymorphism is one of the factors influencing TAC pharmacokinetics, screening for these SNPs prior to liver transplantation might be helpful for individualization of tacrolimus treatment.