title: Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4.
abstract: Renal proximal tubule transporters can play a key role in excretion, pharmacokinetic interactions, and toxicity of immunosuppressant drugs. Basolateral organic anion transporters (OATs) and apical multidrug resistance-associated proteins (MRPs) contribute to the active tubular uptake and urinary efflux of these drugs, respectively. We studied the interaction of 12 immunosuppressants with OAT1- and OAT3-mediated [(3)H]-methotrexate (MTX) uptake in cells, and adenosine triphosphate-dependent [(3)H]-MTX transport in membrane vesicles isolated from human embryonic kidney 293 cells overexpressing human MRP2 and MRP4. Our results show that at a clinically relevant concentration of 10 μM, mycophenolic acid inhibited both OAT1- and OAT3-mediated [(3)H]-MTX uptake. Cytarabine, vinblastine, vincristine, hydrocortisone, and mitoxantrone inhibited only OAT1, whereas tacrolimus, azathioprine, dexamethasone, cyclosporine, and 6-mercaptopurine had no effect on both transporters. Cyclophosphamide stimulated OAT1, but did not affect OAT3. With regard to the apical efflux transporters, mycophenolic acid, cyclophosphamide, hydrocortisone, and tacrolimus inhibited MRP2 and MRP4, whereas mitoxantrone and dexamethasone stimulated [(3)H]-MTX transport by both transporters. Cyclosporine, vincristine, and vinblastine inhibited MRP2 only, whereas 6-mercaptopurine inhibited MRP4 transport activity only. Cytarabine and azathioprine had no effect on either transporter. In conclusion, we charted comprehensively the differences in inhibitory action of various immunosuppressive agents against the 4 key renal anion transporters, and we provide evidence that immunosuppressant drugs can modulate OAT1-, OAT3-, MRP2-, and MRP4-mediated transport of MTX to different extents. The data provide a better understanding of renal mechanisms underlying drug-drug interactions and nephrotoxicity concerning combination regimens with these compounds in the clinic.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Minia University, Minya, Egypt.
authors.forename: Azza A K
authors.initials: AA
authors.lastname: El-Sheikh
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.forename: Heleen M
authors.initials: HM
authors.lastname: Wortelboer
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: Marieke
authors.initials: M
authors.lastname: Schreurs
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D007166:Immunosuppressive Agents; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C114338:organic anion transport protein 3
keywords: ATP; BSA; HBSS; HEK; HEPES; Hank's Balanced Salt Solution; IC(50); MRP; MTX; OAT; TS buffer; Tris-sucrose buffer; adenosine triphosphate; bovine serum albumin; concentration at which 50% inhibition is obtained; human embryonic kidney; hydroxyethylpiperazine ethanesulfonic acid; methotrexate; multidrug resistance-associated protein; organic anion transporter