Polymorphisms of tumor necrosis factor-α, interleukin-10, cytochrome P450 3A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus

Background: Cytokine production in the host immune response after transplantation may contribute to the variable CYP3A-dependent drug disposition. We investigated the effect of TNF-alpha, IL-10, CYP3A5 and ABCB1 polymorphisms on immunosuppressant tacrolimus pharmacokinetics in liver transplant patients. Methods: Genetic polymorphisms in TNF-alpha, IL-10, CYP3A5 and ABCB1 were studied in 70 liver transplant recipients and 70 donors. Tacrolimus dosage and blood concentration were investigated at 1, 2 and 3weeks after transplantation. Results: The IL-10 G-1082A polymorphism in recipients was significantly associated with tacrolimus concentration/dose (C/D) ratios (IL-101082GG < GA < AA) within the first 3weeks posttransplantation (P < 0.05). Recipients with the capacity for low IL-10 production (-1082AA) carrying CYP3A5 non-expressor (CYP3A5*3/*3) liver had the highest C/D ratios (mean: 172.4, 161.7, 160.3 for 1, 2 and 3weeks posttransplantation, respectively); whereas recipients with intermediate or high production of IL-10 (-1082GA or GG) engrafted with CYP3A5 expresser (CYP3A5*1 carrier) liver were found to have the lowest ratios (96.4, 78.0 and 75.4, respectively, P < 0.01). Conclusions: The IL-10 G-1082A and CYP3A5*3 polyrnorphisms may influence the interindividual variability of tacrolimus pharmacokinetics in Chinese liver transplant patients. This finding provided a new interpretation for the variable immunosuprressant disposition after transplantation. (C) 2007 Elsevier B.V. All rights reserved.