CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation

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Abstract
Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear. In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT). The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1. These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.