title: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1.
abstract: Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that adefovir is efficiently transported by the human renal organic anion transporter 1 (hOAT1), a membrane transport protein localized in the kidney, that presumably mediates the accumulation of adefovir in renal proximal tubules. In an effort to look for novel inhibitors of this transport process, we used a cell line stably expressing hOAT1 to demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) efficiently inhibit hOAT1-specific transport of adefovir at clinically relevant concentrations. Diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen were equally or more effective (IC(50) = 0.85-8 microM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC(50) = 8 and 6 microM, respectively) with in vivo nephroprotective effects. Importantly, NSAIDs significantly reduced the shift in adefovir cytotoxicity observed upon hOAT1 expression with ketoprofen and naproxen being 2- to 3-times more effective than probenecid. Transport experiments with [(3)H]ketoprofen and [(3)H]ibuprofen revealed that NSAIDs themselves were not efficiently transported by hOAT1. None of the NSAIDs tested showed any interference with the anti-HIV activity of adefovir. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of adefovir nephrotoxicity.
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Mulato
authors.forename: E S
authors.initials: ES
authors.lastname: Ho
authors.forename: T
authors.initials: T
authors.lastname: Cihlar
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D063065:Organophosphonates; D013329:Structure-Activity Relationship
chemical_list: D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D002352:Carrier Proteins; D063065:Organophosphonates; C053001:adefovir; D000225:Adenine