Effect of cytochrome P450 3A5 polymorphism on the pharmacokinetics of tacrolimus in renal transplant recipients

Abstract

Background Renal transplant is an effective treatment option for end-stage kidney disease and tacrolimus is one of the most commonly used immunosuppressant drugs in renal transplant patients. Tacrolimus is a substrate of cytochrome P450 3A5 (CYP3A5), and a narrow therapeutic index and large inter-individual variability. The objective of this study was to determine the frequency of CYP3A5*3 polymorphism and its effect on the pharmacokinetics of tacrolimus in post-renal transplant patients at Mandalay General Hospital. Methods Three different genotypes of CYP3A5 were determined by polymerase chain reaction-restriction fragment length polymorphism in 54 post-renal transplant recipients. Tacrolimus trough concentrations (C trough ) were measured by enzyme multiplied immunoassay technique following method validation. The apparent clearance (CL/F) was calculated from measured C trough . Results The frequency of CYP3A5*1 allele was 0.24 and that of CYP3A5*3 allele was 0.76 in the study sample. There were a total of 33 CYP3A5 non-expressors (patients with CYP3A5*3/*3 genotype) and 21 CYP3A5 expressors (patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotype), respectively. CL/F was significantly lower in the non-expressor group than in the expressor group (mean±standard deviation, 12.53±5.28 vs. 21.22±5.95 L/hr; P<0.001). The mean C trough and concentration dose ratio (C/D) for tacrolimus in CYP3A5 non-expressors were significantly higher than those in CYP3A5 expressors (C trough , 7.14±2.56 vs. 5.92±1.76 ng/mL; C/D, 6.92±4.11 vs. 2.89±1.85 ng/mL/mg), respectively (P<0.05). Conclusions In this study, 76% of the Myanmar renal transplant recipients carried the CYP3A5*3 allele that was associated with lower functional activity of the CYP3A5 enzyme a lower CL/F of tacrolimus in these Thus, CYP3A5 polymorphism influences the pharmacokinetics of tacrolimus, which may affect the pharmacological response to tacrolimus

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation

“…TAC metabolism varies from patient to patient, thereby affecting TAC blood concentrations, which is referred to as inter-patient variability. The cytochrome P450 (CYP) 3A5 isoenzyme plays a major role in TAC metabolism, showing differences in metabolic characteristics according to genotype ( 9 , 10 ). However, it is difficult to regularly test for the CYP3A5 genotype in all patients in actual clinical practice.…”