title: Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation.
abstract: BACKGROUND
  The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.
  
  
  METHODS
  The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.
  
  
  RESULTS
  The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients' genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes' activities.
  
  
  CONCLUSIONS
  Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug's tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Niš, Serbia.
authors.forename: Nikola Z
authors.initials: NZ
authors.lastname: Stefanović
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia; Clinic of Nephrology, Clinical Centre Niš, Serbia.
authors.forename: Tatjana P
authors.initials: TP
authors.lastname: Cvetković
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Niš, Serbia; Clinic of Nephrology, Clinical Centre Niš, Serbia.
authors.forename: Radmila M
authors.initials: RM
authors.lastname: Veličković-Radovanović
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia.
authors.forename: Tatjana M
authors.initials: TM
authors.lastname: Jevtović-Stoimenov
authors.affiliation: Centre for Medical Biochemistry, Clinical Centre Niš, Serbia.
authors.forename: Predrag M
authors.initials: PM
authors.lastname: Vlahović
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia.
authors.forename: Ivana R
authors.initials: IR
authors.lastname: Stojanović
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Niš, Serbia.
authors.forename: Dušica D
authors.initials: DD
authors.lastname: Pavlović
keywords: ABCB1; CYP3A5; oxidative stress; renal transplantation; tacrolimus; tubular damage