Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus

Xenobiotica. 2013 Mar;43(3):229-35. doi: 10.3109/00498254.2012.713531. Epub 2012 Aug 30.

Abstract

1. The purpose of this study was to investigate the contribution of MRP2 to the efflux of mycophenolic acid (MPA), and its phenyl glucuronide (MPAG) and acyl glucuronide (AcMPAG) metabolites, using Madin-Darby canine kidney II cells stably transfected with human MRP2 gene (MDCKII/MRP2 cells). 2. Compared to parental MDCKII cells, MPAG was significantly translocated from basolateral (BL) to apical (AP) side in MDCKII/MRP2 cells, indicating MPAG is a substrate for MRP2. AcMPAG is highly translocated from BL to AP side in both cells, suggesting that AcMPAG is actively secreted possibly through an efflux transporter other than MRP2. Appreciable translocation of MPA was not observed in MDCKII/MRP2 cells. 3. Furthermore, using MRP2-expressing Sf9 membrane vesicles, the Michaelis-Menten constant (Km) value for MRP2-mediated MPAG transport was calculated at 224.2 ± 42.7 µM. In the vesicle system, cyclosporine, tacrolimus and sirolimus did not inhibit the uptake of MPAG via MRP2. 4. These findings indicate that only MPAG not MPA and AcMPAG is a substrate for MRP2 and that the interaction between MPAG and concomitantly administered immunosuppressive agents does not occur at MRP2 level.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Biological Transport / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Membrane Permeability / drug effects
  • Cyclosporine / pharmacology*
  • Diffusion
  • Dogs
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Glucuronides / metabolism*
  • Humans
  • Madin Darby Canine Kidney Cells
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Mycophenolic Acid / analogs & derivatives*
  • Mycophenolic Acid / metabolism
  • Sirolimus / pharmacology*
  • Tacrolimus / pharmacology*
  • Transport Vesicles / drug effects
  • Transport Vesicles / metabolism

Substances

  • ABCC2 protein, human
  • Glucuronides
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • mycophenolic acid glucuronide
  • Cyclosporine
  • Adenosine Triphosphate
  • Mycophenolic Acid
  • Sirolimus
  • Tacrolimus