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. (December 2022)

• Record Type: Journal Article
• Authors: Coste, Gwendal; Robin, Fabien; Chemouny, Jonathan; Tron, Camille; Le Priol, Jérôme; Bouvet, Régis; Le Vée, Marc; Houssel-Debry, Pauline; Rayar, Michel; Verdier, Marie-Clémence; Roussel, Mikael; Galibert, Marie-Dominique; Bardou-Jacquet, Edouard; Fardel, Olivier; Vigneau, Cécile; Boudjema, Karim; Laviolle, Bruno; Lemaitre, Florian
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 47(2022)
• Publication Date: 2022-12
• Subjects: Tacrolimus -- Solid organ transplantation -- Therapeutic drug monitoring -- Pharmacokinetics -- Drug transporter -- Personalized medicine; TAC tacrolimus -- MMF mycophenolate mofetil -- CS corticosteroids -- PK pharmacokinetic -- TDM therapeutic drug monitoring -- ADR adverse drug reactions -- Cblood whole-blood trough concentration -- PBMC peripheral blood mononuclear cells -- CPBMC peripheral blood mononuclear cells concentration -- P-gp P-glycoprotein -- MRP2 multidrug resistance-associated protein 2 -- CNT3 concentrative nucleoside transporter 3 -- ENT1 equilibrative nucleoside transporter 1 -- ABC ATP binding cassette -- SLC solute carrier -- mRNA messenger ribonucleic acid -- SNP single nucleotide polymorphism -- LTR liver transplant recipient -- KTR kidney transplant recipient -- PD pharmacodynamic -- CPBMC/Cblood peripheral mononuclear cells over blood concentrations ratio -- RT-qPCR reverse transcription quantitative real time polymerase chain reaction; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2022.100473
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: 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 (Cblood ) is mandatory in solid organ transplant recipients. Using peripheral blood mononuclear cells concentrations (CPBMC ) could improve patient outcomes. The poor correlation between Cblood and CPBMC 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 CPBMC/blood 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 CPBMC 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 CPBMC/blood 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. Graphical abstract: Image 1