Combinational Effect of Intestinal and Hepatic CYP3A5 Genotypes on Tacrolimus Pharmacokinetics in Recipients of Living Donor Liver Transplantation

Background. For living donor liver transplantation, the genetic association of CYP3A5 genotype of recipient's native intestine and donor's liver allograft with tacrolimus pharmacokinetics has not been explained completely considering liver regeneration time. The goal of the study was to investigate the longitudinal effects of recipient-donor combinational CYP3A5 genotypes on tacrolimus dose-normalized concentration (C/D ratio) in blood. Methods. Tacrolimus blood concentrations were measured for 58 Korean adult living donor liver transplant recipients on tacrolimus-based immunosuppressants during 4 years of follow-up. CYP3A5 was genotyped for both recipient and donor, and the recipient-donor combinational genetic effect on tacrolimus C/D ratios were evaluated as a function of time after adjusting for covariates including demographics and clinical variables. Results. CYP3A5 expresser recipients grafted from CYP3A5 expresser donors consistently had the least C/D ratio throughout the entire study period, whereas CYP3A5 expresser recipients grafted from CYP3A5 nonexpresser donors had an intermediate, and CYP3A5 nonexpresser recipients grafted from CYP3A5 nonexpresser donors had the largest C/D ratio (all P < 0.01). The CYP3A5 nonexpresser recipients grafted from CYP3A5 expresser donors showed a significant decrease from the largest to the intermediate in C/D ratio for the first month. Conclusions. CYP3A5 genotypes of both recipient and donor were important factors influencing pharmacokinetic variability of tacrolimus. The recipient-donor combinational genetic effect on C/D ratio changed over time after transplantation.