Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule.
The interactions of two antiviral, acyclic nucleoside phosphonates, adefovir and cidofovir, with xenobiotic transporters was studied in intact killifish (Fundulus heteroclitus) renal proximal tubules by using fluorescent substrates, confocal microscopy, and quantitative image analysis. Both drugs reduced in a concentration-dependent manner the transport of fluorescein on the classical organic anion system and transport of fluorescein-methotrexate on multidrug resistance-associated protein 2 (Mrp2). Neither drug inhibited transport of a fluorescent cyclosporin A derivative on P-glycoprotein. Inhibition of Mrp2-mediated transport was abolished by 50 microM p-aminohippurate, indicating that adefovir and cidofovir entered the cells at the basolateral membrane on the classical organic anion transport system (OAT1). Comparison of the inhibitory potencies of the nucleoside phosphonates with other substrates and inhibitors showed them to be moderate inhibitors of OAT1- and Mrp2-mediated transport.
Miller
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Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. miller@niehs.nih.gov
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000378:metabolism; D023781:Fundulidae / Q000502:physiology*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D018613:Microscopy, Confocal; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011339:Probenecid / Q000494:pharmacology; D012076:Renal Agents / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology*
D000225:Adenine; D000998:Antiviral Agents; D000077404:Cidofovir; D003596:Cytosine; D005456:Fluorescent Dyes; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011339:Probenecid; D012076:Renal Agents; D015262:Xenobiotics; C053001:adefovir; C421109:multidrug resistance-associated protein 1