Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

Autor: Rosalinde Masereeuw, Heleen M. Wortelboer, Rick Greupink, Jan B. Koenderink, Jeroen J. M. W. van den Heuvel, Frans G. M. Russel, Marieke Schreurs, Azza A.K. El-Sheikh
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Organic anion transporter 1
Biological Transport
Active
Biomedical Innovation
Organic Anion Transporters
Sodium-Independent
Pharmacology
Mycophenolic acid
Nephrotoxicity
Kidney Tubules
Proximal
Translational Research
Biomedical
Organic Anion Transport Protein 1
Life
Physiology (medical)
medicine
Humans
Drug Interactions
Biology
Mitoxantrone
biology
Multidrug resistance-associated protein 2
Biochemistry (medical)
Public Health
Environmental and Occupational Health
PHS - Pharmacokinetics & Human Studies (tot 2013 daarna KFP)
Transporter
General Medicine
Multidrug Resistance-Associated Protein 2
Vinblastine
HEK293 Cells
Methotrexate
Membrane transport and intracellular motility Renal disorder [NCMLS 5]
biology.protein
Efflux
Multidrug Resistance-Associated Proteins
EELS - Earth
Environmental and Life Sciences
Healthy Living
Immunosuppressive Agents
Membrane transport and intracellular motility Poverty-related infectious diseases [NCMLS 5]
medicine.drug
Zdroj: Translational Research, 6, 162, 398-409
Translational Research, 162, 6, pp. 398-409
Translational Research, 162, 398-409
ISSN: 1931-5244
Popis: Contains fulltext : 125987.pdf (Publisher’s version ) (Closed access) 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 muM, 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.
Databáze: OpenAIRE
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