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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
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1437-4331
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Volume 49, Issue 5

Issues

Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes

Beatriz Tavira / Eliecer Coto Garciá
  • Genética Molecular, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Carmen Díaz-Corte
  • Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain
  • Nefrología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Francisco Ortega
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain
  • Nefrología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Manuel Arias
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Nefrología, Hospital Universitario Valdecilla, Santander, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Armando Torres
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Nefrología y Unidad de Investigación, Hospital Universitario de Canarias, Tenerife, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Juan M. Díaz / Rafael Selgas
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Nefrología, Hospital Universitario La Paz, Madrid, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Carlos López-Larrea
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Inmunología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
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  • De Gruyter OnlineGoogle Scholar
/ Josep M. Campistol
  • Genética Molecular, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
  • Fundación Renal I. Alvarez de Toledo, Madrid, Spain
  • Nefrología, Hospital Clinic, Barcelona, Spain
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/ Victoria Alvarezca /

Abstract

Background: Tacrolimus (Tac) is an immunosuppressive drug used to prevent post-transplant (PT) organ rejection. Continuous Tac monitoring is necessary to adjust the dose and prevent toxicity or rejection. Tac is metabolized by cytochrome-P450 (CYP) enzymes, and variation at the CYP and other drug metabolizing enzymes could influence Tac bio-availability and dose requirements. Our aim was to define the effect of DNA variants at 16 drug metabolising enzymes on Tac dose in patients with kidney transplants.

Methods: The REDINREN Pharmacogenetics Project was a multicenter study designed to evaluate the effect of DNA polymorphisms on Tac dose requirements. A total of 200 patients who received a first cadaveric kidney and Tac as primary immunosuppressive drug were genotyped for 96 DNA polymorphisms on 16 genes. Significant associations were further replicated in a second group of 200 patients. The Tac daily dose was adjusted to achieve a blood concentration of 10–15 ng/mL in the period 0–3 months PT, and 5–10 ng/mL thereafter. The dose of tacrolimus dose and blood concentrations were compared between genotypes at 1 week, 6 months, and 1 year PT.

Results: The CYP3A5 genotype (SNP rs776746) was the strongest predictor of Tac dose requirements. Patients who were CYP3A5*3*3 (CYP3A5 non-expressors) received significantly higher Tac dose at 1 week, 6 months, and 1 year PT (p<0.0001). At 1 week, 41% of the CYP3A5 non-expressors achieved target blood concentrations compared to 26% of the CYP3A5 expressors (p=0.007). We also found a significant effect of CYP3A4 genotype (SNP rs2740574) on Tac dose requirements in patients who were CYP3A5 non-expressors. None of the other polymorphisms were related to Tac dose requirements or modified the effect of the CYP3A5 genotype.

Conclusions: rs776746 (CYP3A5) and rs2740574 (CYP3A4) were the only SNPs associated with Tac dosage. The genotyping of these polymorphisms could be a useful pharmacogenetic tool to determine the Tac dose immediately after transplantation.

Keywords: cytochrome P450; pharmacokinetics; pharmacogenetics; renal transplantation; tacrolimus

About the article

Corresponding author: Eliecer Coto García, Genética Molecular, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain Phone/Fax: +(34)985107968


Received: 2010-09-23

Accepted: 2010-12-14

Published in Print: 2011-05-01


Citation Information: Clinical Chemistry and Laboratory Medicine, Volume 49, Issue 5, Pages 825–833, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2011.143.

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