Drug transporters are implicated in the diffusion of tacrolimus into the T lymphocyte in kidney and liver transplant recipients: Genetic, mRNA, protein expression, and functionality

Gwendal Coste (1, 2, 3) , Fabien Robin (3) , Jonathan Chemouny (1, 3) , Camille Tron (1, 3) , Jérôme Le Priol (3) , Regis Bouvet (4, 3) , Marc Le Vée (1, 3) , Pauline Houssel‐debry (2, 3) , Michel Rayar (2, 3) , Marie-Clémence Verdier (1, 3) , Mikaël Roussel (5, 3) , Marie-Dominique Galibert (6, 3) , Edouard Bardou-Jacquet (2, 3) , Olivier Fardel (1, 3) , Cécile Vigneau (1, 3) , Karim Boudjema (1, 3) , Bruno Laviolle (1, 3, 2) , Florian Lemaitre (1, 3, 2)

1 Irset - Institut de recherche en santé, environnement et travail
2 CIC - Centre d'Investigation Clinique [Rennes]
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
4 Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes]
5 MOBIDIC - Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer
6 IGDR - Institut de Génétique et Développement de Rennes

Because of a narrow therapeutic index and a wide inter- and intra-patient variability, therapeutic drug monitoring of the immunosuppressant drug tacrolimus (TAC) based on whole-blood concentrations (C) is mandatory in solid organ transplant recipients. Using peripheral blood mononuclear cells concentrations (C) could improve patient outcomes. The poor correlation between C and C makes hypothesize that drug transporters are implicated in the intracellular accumulation of TAC. The aim of this work was therefore to clinically study: i) the role of genetic variants and ii) the effect of mRNA and protein expression of 4 drug transporters on the TAC C ratio. In addition, functional in vitro experiments were performed to mechanistically validate the clinical observations. Genetic variants of ABCB1/P-gp and SLC28A3/CNT3 did not influence TAC C in liver transplant recipients (LTR). ABCC2/MRP2 at the mRNA level; ABCB1/P-gp, SLC28A3/CNT3 and SLC29A1/ENT1 at the protein level; correlated with the C in kidney and LTR. In vitro results suing transporter-expressing cells confirmed that TAC is substrate of P-gp but not MRP2, whereas experiments remained inconclusive for CNT3 and ENT1. In conclusion, the genetic-transcription-protein-functional approach presented in this work provides new insights in the understanding of TAC transport at the T lymphocyte plasma membrane.

Mots clés: Drug transporter; Personalized medicine; Pharmacokinetics; Solid organ transplantation; Tacrolimus; Therapeutic drug monitoring

Domaines: Sciences du Vivant [q-bio]

Gwendal Coste, Fabien Robin, Jonathan Chemouny, Camille Tron, Jérôme Le Priol, et al.. Drug transporters are implicated in the diffusion of tacrolimus into the T lymphocyte in kidney and liver transplant recipients: Genetic, mRNA, protein expression, and functionality. Drug Metabolism and Pharmacokinetics, 2022, 47, pp.100473. ⟨10.1016/j.dmpk.2022.100473⟩. ⟨hal-03800094⟩