Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus

• Published in: Translational research : the journal of laboratory and clinical medicine 2014-07, Vol.164 (1), p.46-56
• Main Authors: El-Sheikh, Azza A.K, Koenderink, Jan B, Wouterse, Alfons C, van den Broek, Petra H.H, Verweij, Vivienne G.M, Masereeuw, Rosalinde, Russel, Frans G.M
• Format: Article
• Language: English
• Subjects: Animals; Cyclosporine - metabolism; Cyclosporine - pharmacokinetics; Drug Interactions; Gene Expression Regulation - drug effects; Glucuronides - metabolism; HEK293 Cells; Humans; Internal Medicine; Kidney - metabolism; Male; Mice; Mice, Knockout; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Mycophenolic Acid - metabolism; Mycophenolic Acid - pharmacokinetics; Organ Culture Techniques; Rats; Rats, Wistar; Tacrolimus - metabolism; Tacrolimus - pharmacokinetics
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2014.01.006

Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 μM ( P