The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation.

It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CYP3A5*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.

These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.

The enterocyte MDR1 mRNA level was suggested to be a risk factor for acute cellular rejection and death after surgery. Therefore obtaining a sufficient tacrolimus blood level via this molecular information-based initial dosage adjustment may enable the episode of acute cellular rejection after liver transplantation to be reduced.