The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1

Nephrotoxicity is the dose-limiting clinical adverse effect of cidofovir an d adefovir, two potent antiviral therapeutics. Because renal uptake likely plays a role in the etiology of cidofovir- and adefovir-associated nephroto xicity, we attempted to identify a renal transporter capable of interacting with these therapeutics. A cDNA clone was isolated from a human renal libr ary and designated human organic anion transporter 1 (hOAT1). Northern anal ysis detected a specific 2.5-kilobase pair hOAT1 transcript only in human k idney. However, reverse transcription-polymerase chain reaction revealed hO ATI expression in human brain and skeletal muscle, as well. Immunoblot anal ysis of human kidney cortex demonstrated that hOATI is an 80- to 90-kilodal ton heterogeneous protein modified by abundant N-glycosylation. Xenopus lae vis oocytes expressing hOATI supported probenecid-sensitive uptake of [H-3] p-aminohippurate (K-m = 4 mu M), which was trans-stimulated in oocytes prel oaded with glutarate. Importantly, both hOAT1 and rat renal organic anion t ransporter 1 (rROAT1) mediated saturable, probenecid-sensitive uptake of ci dofovir, adefovir, and other nucleoside phosphonate antivirals. The affinit y of hOAT1 toward cidofovir and adefovir (K-m = 46 and 30 mu M, respectivel y) was 5- to g-fold higher compared with rROAT1 (K-m = 238 and 270 mu M, re spectively). These data indicate that hOATI may significantly contribute to the accumulation of cidofovir and adefovir in renal proximal tubules and, thus, play an active role in the mechanism of nephrotoxicity associated wit h these antiviral therapeutics.