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

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2007-09, Vol.22 (9), p.2497-2503
• Main Authors: Wolff, Natascha A., Burckhardt, Birgitta C., Burckhardt, Gerhard, Oellerich, Michael, Armstrong, Victor W.
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Biological Transport - drug effects; Dose-Response Relationship, Drug; Emergency and intensive care: renal failure. Dialysis management; glucuronide mycophenolate metabolites; Glucuronides - metabolism; Glucuronides - pharmacology; hNaDC3; hOAT1/3; Humans; Intensive care medicine; kidney; Kidney - drug effects; Kidney - metabolism; Kidneys; Kinetics; Medical sciences; Membranes - drug effects; mycophenolic acid; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - metabolism; Mycophenolic Acid - pharmacology; Nephrology. Urinary tract diseases; Organic Anion Transport Protein 1 - antagonists & inhibitors; Organic Anion Transporters, Sodium-Independent - antagonists & inhibitors; Organic Anion Transporters, Sodium-Independent - metabolism; Succinic Acid - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; transport; Tumors of the urinary system; Xenopus; Xenopus laevis
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfm219

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 μM, respectively). Human OAT3, but not hOAT1, was additionally inhibited by both glucuronide metabolites of MPA in a concentration-dependent manner (IC50 15.2 μM for MPAG and 2.88 μM 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.