Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus.
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 < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 ± 0.3 μM to 1.33 ± 0.01 μM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion.
Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt.
Azza A K
AA
El-Sheikh
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Jan B
JB
Koenderink
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Alfons C
AC
Wouterse
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Petra H H
PH
van den Broek
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Vivienne G M
VG
Verweij
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Rosalinde
R
Masereeuw
Department of Pharmacology and Toxicology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. Electronic address: Frans.Russel@radboudumc.nl.
Frans G M
FG
Russel
D000818:Animals; D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000378:metabolism / Q000493:pharmacokinetics*
D016572:Cyclosporine; D020719:Glucuronides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D016559:Tacrolimus; C000715087:ABCC2 protein, human