The relationship between tacrolimus concentration-dose ratio and genetic polymorphism in patients subjected to renal transplantation

Nemanja Rančić; Neven Vavić; Bojana Cikota-Aleksić; Zvonko Magić; Momir Mikov; Dubravko Bokonjić; Zoran Šegrt; Viktorija Dragojević-Simić

doi:10.2298/VSP151230329R

Nemanja Rančić University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Neven Vavić Centre for Transplantation of Solid Organs, Military Medical Academy, Belgrade, Serbia
Bojana Cikota-Aleksić Military Medical Academy, Institute for Medical Research, Belgrade, Serbia
Zvonko Magić Military Medical Academy, Institute for Medical Research, Belgrade, Serbia
Momir Mikov University of Novi Sad, Faculty of Medicine, Institute for Pharmacology, Novi Sad, Serbia
Dubravko Bokonjić National Poison Control Centre, Medical Faculty Military Medical Academy, University of Defense, Belgrade, Serbia
Zoran Šegrt Management of the Military Medical Academy, Medical Faculty Military Medical Academy, University of Defence, Belgrade, Serbia
Viktorija Dragojević-Simić Centre for Clinical Pharmacology; Medical Faculty Military Medical Academy, University of Defence, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP151230329R

Keywords: kidney transplantation;, tacrolimus;, dose-response relationship, drug;, polymorphism, genetic.

Abstract

Background/Aim. Tacrolimus concentration-dose ratio as a potential therapeutic drug monitoring strategy was suggested to be used for the patients subjected to renal transplantation. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio, suggested to be used as a therapeutic drug monitoring strategy and the polymorphisms of genes encoding the most important enzymes, such as CYP3A5 and CYP3A4, as well as the transporter P-glycoprotein, for its metabolism and elimination. Methods. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 Real-Time PCR System by assessing allelic discrimination based on TaqMan^® methodology. Results. Patients (n = 13) who were treated with less than 2 mg of tacrolimus/day (0.024 ± 0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/mL/mg/kg. In this group, 84.62% patients had CYP3А5 *3*3 allele. All of these patients had CYP3А4 *1*1/*1*1B allele. Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant, while 69.23% of our patients had CC and CT gene variants. Conclusion. Tacrolimus concentration-dose ratio greater than 150 ng/mL/mg/kg is cut-off value in patients subjected to renal transplantation which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein.

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