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Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation

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Abstract

Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect.

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Authors and Affiliations

  1. Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes University Hospital, Rennes, France

    Camille Tron, Florian Lemaitre, Antoine Petitcollin, Marie-Clémence Verdier & Eric Bellissant

  2. Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, Rennes 1 University, Rennes, France

    Camille Tron, Florian Lemaitre, Antoine Petitcollin, Marie-Clémence Verdier & Eric Bellissant

  3. Clinical Investigation Centre, CIC-P Inserm 1414, Rennes, France

    Camille Tron, Florian Lemaitre, Antoine Petitcollin, Marie-Clémence Verdier & Eric Bellissant

  4. Department of Molecular Genetics, Pharmacogenetics, and Hormonology, Hôpital Bicêtre, Groupe Hospitalier Paris Sud, AP-HP, Le Kremlin Bicêtre, France

    Céline Verstuyft

  5. INSERM UMR1178, Team (Depression and Antidepressants), Faculty of Medicine Paris-Sud, Paris-Sud University, Le Kremlin Bicêtre, France

    Céline Verstuyft

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  1. Camille Tron
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CT wrote the manuscript, and FL, CV, AP, MCV, and EB fully reviewed the manuscript.

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Camille Tron, Florian Lemaitre, Céline Verstuyft, Antoine Petitcollin, Marie-Clémence Verdier, and Eric Bellissant have no conflicts of interest to declare that are relevant to the content of this review.

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Tron, C., Lemaitre, F., Verstuyft, C. et al. Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation. Clin Pharmacokinet 58, 593–613 (2019). https://doi.org/10.1007/s40262-018-0717-7

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