MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood
| العنوان: | MRP4 is responsible for the efflux transport of mycophenolic acid β- |
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| المؤلفون: | Joseph Berthier, Nicolas Picard, François-Ludovic Sauvage, Pierre Marquet, Benjamin Chantemargue, Hélène Arnion, Gabin Fabre, Franck Saint-Marcoux, Mehdi Benmameri, Patrick Trouillas |
| المصدر: | Xenobiotica. 51:105-114 |
| بيانات النشر: | Informa UK Limited, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Health, Toxicology and Mutagenesis, Pharmacology, Kidney, Toxicology, 030226 pharmacology & pharmacy, Biochemistry, Mycophenolic acid, 03 medical and health sciences, Glucuronides, 0302 clinical medicine, medicine, Humans, Gastrointestinal tract, Chemistry, Membrane Transport Proteins, Biological Transport, General Medicine, Mycophenolic Acid, Molecular Docking Simulation, stomatognathic diseases, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocytes, Transplant patient, Efflux, Multidrug Resistance-Associated Proteins, Glucuronide, medicine.drug |
| الوصف: | Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-d glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented. The aim of the present study was to explore these interactions with the basolateral hepatic MRP4 transporter. The inhibition of the MRP4-driven transport by various drugs which can be concomitantly prescribed was also evaluated. In vitro experiments using vesicles overexpressing MRP4 showed an ATP-dependent transport of MPAG driven by MRP4 (Michaelis-Menten constant of 233.9 ± 32.8 µM). MPA was not effluxed by MRP4. MRP4-mediated transport of MPAG was inhibited (from -43% to -84%) by ibuprofen, cefazolin, cefotaxime and micafungin. An in silico approach based on molecular docking and molecular dynamics simulations rationalized the mode of binding of MPAG to MRP4. The presence of the glucuronide moiety in MPAG was highlighted as key, being prone to make electrostatic and H-bond interactions with specific residues of the MRP4 protein chamber. This explains why MPAG is a substrate of MRP4 whereas MPA is not. |
| تدمد: | 1366-5928 0049-8254 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad854d066575c7d75375dc3eea9deab3Test https://doi.org/10.1080/00498254.2020.1813352Test |
| رقم الانضمام: | edsair.doi.dedup.....ad854d066575c7d75375dc3eea9deab3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13665928 00498254 |
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