Cytochrome P450 3A4[asterisk]1B as pharmacogenomic predictor of tacrolimus pharmacokinetics and clinical outcome in the liver transplant recipients

ABSTRACT

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 CYP3A4[asterisk]1B 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 CYP3A4[asterisk]1B on tacrolimus dosing and clinical outcome in liver transplant recipients. 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. 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. Based on our results, it may be concluded that CYP3A4[asterisk]1B of recipient is an important factor influencing pharmacokinetic of tacrolimus, as patients with CYP3A4[asterisk]1B polymorphism may require lower tacrolimus doses to maintain therapeutic levels. The dose reduction may not affect clinical outcomes after liver transplant