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.