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Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype

The Pharmacogenomics Journal volume 17, pages 556–562 (2017)Cite this article

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Abstract

The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARA and APOA5 were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1 diplotype and time after transplantation. The effect of ABCB1 diplotype was small but strongly accentuated in CYP3A4*22 carriers and non-existent in CYP3A5 expressors. ABCC2 diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.

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Acknowledgements

We thank A Herelixka for managing the clinical database, T Coopmans, J de Loor, M Dekens and T Van Brussel for their technical assistance and our study nurses C Beerten, J De Vis, M Dubois and H Wielandt for their work in the Biobank program.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, KU Leuven—University of Leuven, Leuven, Belgium

    T Vanhove & D R J Kuypers

  2. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium

    T Vanhove & D R J Kuypers

  3. Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven—University of Leuven, Leuven, Belgium

    P Annaert

  4. Vesalius Research Center, VIB, Leuven, Belgium

    D Lambrechts

  5. Department of Oncology, Laboratory for Translational Genetics, KU Leuven—University of Leuven, Leuven, Belgium

    D Lambrechts

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Correspondence to D R J Kuypers.

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DK has received consulting fees and research grants from Astellas. The remaining authors declared no conflict of interest.

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Vanhove, T., Annaert, P., Lambrechts, D. et al. Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype. Pharmacogenomics J 17, 556–562 (2017). https://doi.org/10.1038/tpj.2016.49

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