Cytochrome P450 3A4FNx011B as pharmacogenomic predictor of tacrolimus pharmacokinetics and clinical outcome in the liver transplant recipients.

BACKGROUND AND AIMS: Tacrolimus is a macrolide immunosuppressant used for prevention of allograft rejection in organ transplantation and metabolized in the liver and intestine by cytochrome P450 3A4 (CYP3A4) enzyme. A single nucleotide polymorphism (SNP) in the CYP3A4 promoter region has been identified. It has been shown that the presence of CYP3A4FNx011B allele (variant GG) is associated with a reduced catalytic activity of CYP3A4 in vivo. The aim of this study was to determine the role of CYP3A4FNx011B on tacrolimus dosing and clinical outcome in liver transplant recipients.

SUBJECTS AND METHODS: Forty-eight liver transplant recipients were stratified according to the genotype. There were 32 wild-type (AA) patients and 5 homozygous variant (GG) and 11 (AG) heterozygous. Tacrolimus doses and trough concentrations as well as phenotypic data were collected in the first 10 days of the transplant.

RESULTS: The tacrolimus concentration was significantly higher in the wild (AA) group as compared to homozygous variant (GG) and heterozygous (AG) patients. Homozygous variant (GG) group had significantly lower dose requirements. However, no significant difference was observed in the concentration/dose ratio between all groups.

CONCLUSIONS: Based on our results, it may be concluded that CYP3A4FNx011B of recipient is an important factor influencing pharmacokinetic of tacrolimus, as patients with CYP3A4FNx011B polymorphism may require lower tacrolimus doses to maintain therapeutic levels. The dose reduction may not affect clinical outcomes after liver transplant.