Influence of CYP3A5 Gene Polymorphisms of Donor Rather than Recipient to Tacrolimus Individual Dose Requirement in Liver Transplantation

Abstract

Tacrolimus is a widely used immunosuppressant in organ transplantation, but it is characterized by a narrow therapeutic index and high interindividual variations of its pharmacokinetics. Tacrolimus is a substrate for CYP3A. It has been conjectured that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. The objective of this study was to evaluate the contribution of polymorphisms of the donor and recipient CYP3A5 gene on tacrolimus disposition in liver transplantation. Fifty-three liver transplant recipients treated with tacrolimus were enrolled in this study. Tacrolimus dosage and blood trough concentration were investigated at 1 week, 2 weeks, and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A5 gene. The concentration/dose (C/D) ratios in patients with *1/*1(*1/*3) genotype donor were significantly lower than in patients with *3/*3 genotype donor at 2 weeks (P = 0.036) and 1 month (P = 0.021), but not at 1 week posttransplantation. Combination analysis showed that such significance still existed between CYP3A5 expressor group and nonexpressor group for both donor and recipient genotype. Also differences of C/D ratio between CYP3A5 expressor and nonexpressor donors in nonexpressor recipients were larger than those between recipients in nonexpressor donors. The large interindividual variation of tacrolimus dose requirement is influenced by the metabolic activity of CYP3A5. Polymorphisms of the donor CYP3A5 gene seem to contribute more to such variation than the recipient. A larger population and further studies are needed to explore the exact mechanisms for tacrolimus pharmacokinetics.