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.
- Klíčová slova
- MPA, MPAG, MRP4, drug–drug interactions, molecular docking,
- MeSH
- biologický transport MeSH
- glukuronidy metabolismus MeSH
- hepatocyty metabolismus MeSH
- játra metabolismus MeSH
- kyselina mykofenolová analogy a deriváty metabolismus MeSH
- ledviny metabolismus MeSH
- lidé MeSH
- membránové transportní proteiny metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glukuronidy MeSH
- kyselina mykofenolová MeSH
- membránové transportní proteiny MeSH
- mycophenolic acid glucuronide MeSH Prohlížeč
- proteiny spojené s mnohočetnou rezistencí k lékům MeSH
