www.medfak.ni.ac.rs/amm 33 Original article UDC: 577.2:616.61-089.83 doi:10.5633/amm.2013.0105 SIGNIFICANCE OF CYP3A5 GENE POLYMORPHISM IN SERBIAN RENAL TRANSPLANT PATIENTS Nikola Stefanović, Tatjana Cvetković, Radmila Veličković-Radovanović, Tatjana Jevtović-Stoimenov, Dijana Stojanović and Nataša Živković Tacrolimus (FK-506) is a part of most immunosuppressive protocols after kidney transplantation because it significantly affects the survival of transplanted organs in post - transplantation period. FK-506 is characterized by a narrow therapeutic index and large interindividual variability in pharmacokinetics. Partly, these variations can be explained by 6986A>G polymorphism CYP3A5 gene. As a substrate for CYP3A5 isoenzyme, FK–506 has a different elimination rate amnog individuals, which is caused by CYP3A5 gene polymorphism. The primary objective of this study was to investigate the frequency of CYP3A5 gene polymorphism (6986A>G) in kidney transplant patients and comparison with the healthy volunteers. The second objective of this study was to determine the influence of the investigated polymorphism on FK–506 dosage regimen one month after kidney transplantation. Pharmacogenetic retrospective study included 121 examinees - 60 patients with renal transplant and 60 healthy volunteers. Patients have routine determination of drug concentration at the Clinic of Nephrology, Clinical Center Niš, Serbia. PCR method (Ashavaid TF et al.) was used to determine the polymorphism of CYP3A5 gene. Our study did not show statistically significant differences in allele (p=0.616) and genotype (p=0.602) frequencies between the studied polymorphism in renal transplant patients and healthy volunteers. A statistically significant difference was found between patients with different genotypes of CYP3A5 regarding dose (p=0.001), weight adjusted dose (p=0.005), and dose normalized level of FK–506 (p=0.039) one month after transplantation. Patients with kidney transplant and healthy subjects in Serbian population did not show difference in the frequency of alleles of CYP3A5 gene. CYP3A5 gene polymorphism affects the dose regimen of tacrolimus one month after kidney transplantation. Acta Medica Medianae 2013;52(1):33-38. Key words: tacrolimus, CYP3A5 polymorphism, pharmacogenetics, kidney transplant University of Niš, Faculty of Medicine, Niš, Serbia Contact: Nikola Stefanović Faculty of Medicine Niš, Department of Pharmacology Bulevar dr. Zorana inđića br. 81 18000 Niš, Serbia E-mail: snikola84@gmail.com Introduction Tacrolimus (FK-506) is a part of most immuno- suppressive protocols after kidney transplantation. It significantly affects the survival of transplanted organs in post-transplantation period, but also it can cause adverse effects and toxicity. Due to the narrow therapeutic index and large inter- individual variability in pharmacokinetics, therapeutic drug monitoring is required in order to reduce the toxicity and improve efficiency. Consequences of both, under-immunosuppression or over-immuno- suppression can be potentially severe. Under- immunosuppression increases the risk of immune- mediated rejection of transplanted organs, which leads to potential organ loss. Otherwise, over- immunosuppression increases the risk of serious infections and malignancies, as well as a number of complications such as nephrotoxicity and post- transplantation diabetes mellitus (1-3). Cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) are the major enzymes in the metabolism of FK–506. Functional CYP3A4 is located in the liver and small intestine of each individual. Conversely, functionally active CYP3A5 only exists in some individuals (expressers). Otherwise, CYP3A5 is expressed in the liver, small intestine and kidney. Expresser has one of the wild-type alleles (CYP3A5*1) and may carry one of the two possible genotypes, CYP3A5*1/*1 or *1/*3. Non–expressers are homozygous for mutant allel, CYP3A5*3/*3. Differences among individuals are resulted in 6986A>G polymorphism of CYP3A5 gene, which leads to a failure in the synthesis of functional enzyme. Earlier studies have shown that CYP3A5 6986A>G polymorphism influences the pharmaco-kinetics of FK-506 (4-7). As a substrate for CYP3A5 isoenzyme, FK–506