title: Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function.
abstract: The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Nis, Nis 18000, Serbia.
authors.forename: Nikola Z
authors.initials: NZ
authors.lastname: Stefanović
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Nis, Nis 18000, Serbia ; Clinic of Nephrology, Clinical Centre Nis, Nis 18000, Serbia.
authors.forename: Tatjana P
authors.initials: TP
authors.lastname: Cvetković
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Nis, Nis 18000, Serbia.
authors.forename: Tatjana M
authors.initials: TM
authors.lastname: Jevtović-Stoimenov
authors.affiliation: Department of Medical Statistics, Faculty of Medicine, University of Nis, Nis 18000, Serbia.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Ignjatović
authors.affiliation: Clinic of Nephrology, Clinical Centre Nis, Nis 18000, Serbia.
authors.forename: Goran J
authors.initials: GJ
authors.lastname: Paunović
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Nis, Nis 18000, Serbia ; Clinic of Nephrology, Clinical Centre Nis, Nis 18000, Serbia.
authors.forename: Radmila M
authors.initials: RM
authors.lastname: Veličković
keywords: ATP-binding cassette transporter B1; cytochrome P450 3A5; renal function; renal transplantation; tacrolimus