Abstract
Background: Tacrolimus pharmacokinetics has large inter-individual variability. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients. Methods: Steady-statetacrolimus concentrations at 0, 1, 2, 4 and 6 h were measured. Pharma- cokinetic parameters were estimated with a one-compartment linear model using WinNonlin 6.1 program. DNA from donor liver and recipient blood samples were genotyped for CYP3Aand ABCB1 polymorphisms. Results: A total of 13 donors and 17 recipients were included. Donor genotypes influenced tacrolimus trough concentration-to-dose (C0/D) ratio only at Week 1. Patients with liver grafts from CYP3A5 expressors (*1*1 and *1*3) achieved lower mean C0/D ratio than those with grafts from non-expressors (*3*3) (64.48 versus 129.21 (mcg/L)/(mg/kg/day), P = 0.040). Hence, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P = 0.045). Recipient with ABCB1-C3435T genotype TT demonstrated higher apparent oral clearance of tacrolimus as compared to genotype CC (17.7 versus7.9 L/h, P = 0.033). Conclusions: Donor liver CYP3Apolymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period.
Highlights
Over the years, tacrolimus has become well established as the primary immunosuppressant employed by most liver transplant centers
This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients
DNA from donor liver and recipient blood samples were genotyped for cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms
Summary
Tacrolimus has become well established as the primary immunosuppressant employed by most liver transplant centers. *Gene Polymorphisms on Tacrolimus Dosing & Pharmacokinetics. Studies have shown that the gene polymorphisms of CYP3A5 and ABCB1 contribute to the variability of tacrolimus dose-adjusted concentrations [4,5,8,9]. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients. DNA from donor liver and recipient blood samples were genotyped for CYP3A and ABCB1 polymorphisms. Donor genotypes influenced tacrolimus trough concentration-to-dose (C0/D) ratio only at Week 1. The dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P = 0.045). Conclusions: Donor liver CYP3A polymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period
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