Mycophenolic acid (MPA) and its glucuronide metabolites interact with transport systems responsible for excretion of organic anions in the basolateral membrane of the human kidney.
BACKGROUND
Mycophenolic acid (MPA), the active moiety of the prodrug mycophenolate mofetil, is widely used in immunosuppressive regimens after kidney, liver or heart transplantation. MPA is metabolized predominantly to the inactive 7-O-glucuronide (MPAG). A minor fraction is converted to the pharmacologically active acyl glucuronide (AcMPAG). All compounds ultimately are eliminated via the kidneys. Due to their structures, MPA and its metabolites are candidate substrates for the human organic anion transporters 1 (OAT1) and 3 (OAT3) as well as for the Na+-dicarboxylate cotransporter 3 (NaDC3).


METHODS
Human (h)OAT1, hOAT3 and hNaDC3 were expressed from in vitro synthesized cRNA in collagenase-defolliculated Xenopus laevis oocytes. On day 3 post-injection, measurements were made of (i) substrate-associated currents using MPA and MPAG (only in hNaDC3-expressing oocytes) and (ii) uptake of [3H]p-aminohippurate (hOAT1) or [3H]estrone sulfate (hOAT3) in the absence or presence of either MPA, MPAG or AcMPAG.


RESULTS
In hNaDC3-expressing oocytes at -60 mV, MPA (0.1 mM) as well as MPAG (0.1 mM) induced inward currents that were 17 and 25% of the currents evoked by succinate (1 mM). Vice versa, currents induced by succinate (1 mM) were partially inhibited by MPA and MPAG. hOAT1 and hOAT3 were potently inhibited by MPA (IC50 1.24 and 0.52 microM, respectively). Human OAT3, but not hOAT1, was additionally inhibited by both glucuronide metabolites of MPA in a concentration-dependent manner (IC50 15.2 microM for MPAG and 2.88 microM for AcMPAG), consistent with a preference of hOAT3 for more bulky substrates compared with hOAT1.


CONCLUSIONS
MPA and its metabolites potently interact with renal organic anion transporters hOAT1 and hOAT3, and thereby may interfere with the renal secretion of antiviral drugs, cortisol and other organic anions.
Wolff
Natascha A
NA
Zentrum Physiologie und Pathophysiologie, Georg August Universität Göttingen, Germany. natascha.wolff@uni-wh.de
Burckhardt
Birgitta C
BC
Burckhardt
Gerhard
G
Oellerich
Michael
M
Armstrong
Victor W
VW
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008566:Membranes / Q000187:drug effects; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019802:Succinic Acid / Q000494:pharmacology; D014981:Xenopus
D020719:Glucuronides; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D019802:Succinic Acid; D009173:Mycophenolic Acid