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. 2015 Oct;34(4):422-430.
doi: 10.1515/jomb-2015-0001. Epub 2015 Sep 19.

Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation

Nikola Z Stefanović  1 , Tatjana P Cvetković  2 , Radmila M Veličković-Radovanović  3 , Tatjana M Jevtović-Stoimenov  4 , Predrag M Vlahović  5 , Ivana R Stojanović  4 , Dušica D Pavlović  4
Affiliations

Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation

Nikola Z Stefanović et al. J Med Biochem. 2015 Oct.

Abstract
in English, Serbian

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.

Uvod: Primarni cilj ovog rada bio je procena uticaja citohrom P450 (CYP) 3A5 (6986A>G) i ABCB1 (3435C>T) polimorfizama na dozni režim i izloženost takrolimusu (TAC). Sekundarni cilj bio je procena uticaja doznog režima TAC i ispitivanih polimorfizama na renalni oksidativni stres, kao i na urinarnu aktivnost tubularnih ektoenzima u dugoročnom periodu nakon transplantacije. Takođe, mi smo imali za cilj da odredimo povezanost između renalnog oksidativnog stresa i markera tubularnog oštećenja kod pacijenata sa transplantiranim bubregom.

Metode: Istraživanje je uključivalo 72 pacijenata, koji su bili na TAC imunosupresivnom režimu. Alelspecifični PCR metod je korišćen u cilju određivanja polimorfizama. Mi smo određivali nivo tiobarbituratna kiselina reaktivnih supstanci (TBARS) i reaktivnih karbonilnih grupa (RCD) u urinu u cilju procene oksidativnog stresa i aktivnosti ektoenzima (N-acetil-β-D-glukozaminidaza, aminopeptidaza N i dipeptidil peptidaza IV) u urinu, kao markere oštećenja tubula.

Rezultati: Nosioci CYP 3A5*1 alela imali su statistički veće dnevne doze TAC u poređenju sa nosiocima CYP *3/*3 genotipa, kao i nosioci C alela ABCB1 genskog polimorfizma u poređenju sa nosiocima TT genotipa. Takođe, nije bilo razlika u nivoima TBARS, RCD i aktivnostima ektoenzima između različitih genotipova pacijenata. Naši rezultati pokazali su značajne korelacije između urinarnog TBARS i RCD i aktivnosti ektoenzima.

Zaključak: Naši rezultati ukazuju na to da CYP 3A5 i ABCB1 3435 polimorfizam mogu uticati na dnevnu dozu TAC, ali ne i na tubularnu toksičnost izazvanu lekom. Pored toga, oštećenje tubula može biti udruženo sa povećanim renalnim oksidativnim stresom.

Keywords: ABCB1; CYP3A5; oxidative stress; renal transplantation; tacrolimus; tubular damage.

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Figures

Figure 1
Figure 1
Serum creatinine level (A) and GFR (B) in relation to dosage regimen of TAC, CYP 3A5 and ABCB1 polymorphism.
See this image and copyright information in PMC

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