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European Journal of Clinical Pharmacology

, Volume 69, Issue 3, pp 385–393 | Cite as

ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients

  • Montserrat García
  • Rosa María Macías
  • Juan José Cubero
  • Julio Benítez
  • Francisco Caravaca
  • Guillermo GervasiniEmail author
Pharmacogenetics

Abstract

Purpose

There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients

Methods

The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation.

Results

Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3–13.9, p = 0.02 and OR 3.6, 95 % CI 1.1–11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1–10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes.

Conclusions

ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug’s trough blood concentrations.

Keywords

ABCB1 CYP3A Polymorphisms Renal transplant Cyclosporine 

Notes

Acknowledgements

This work has been supported in part by grant GR10022 from Junta de Extremadura, Consejería de Economía, Comercio e Innovación, Mérida, Spain and grant PRIS11003 from FUNDESALUD, Mérida, Spain.

Conflict of interest statement

None.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Montserrat García
    • 1
  • Rosa María Macías
    • 2
  • Juan José Cubero
    • 2
  • Julio Benítez
    • 1
  • Francisco Caravaca
    • 2
  • Guillermo Gervasini
    • 1
    Email author
  1. 1.Department of Surgical and Medical Therapeutics, Division of Pharmacology, Medical SchoolUniversity of ExtremaduraBadajozSpain
  2. 2.Service of NephrologyInfanta Cristina HospitalBadajozSpain

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