Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Abstract

Objectives: Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein.

Materials and Methods: We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T].

Results: Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found.

Conclusions: Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.