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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Are Protective against the In Vitro Cytotoxicity of Adefovir (ADV) Mediated by the Human Renal Organic Anion Transporter 1 (hOAT1) A. MULATO, E. HO, and T. CIHLAR*. Giead Sci., Foster City, CA ADV is an HIV reverse transcriptase inhibitor with a unique resistance profile currently undergoing regulatory review. While on prolonged ADV therapy, some patients may develop nephrotoxicity associated with changes in laboratory markers of renal functions that is reversible upon drug discontinuation. hOAT1, a membrane transport protein localized specifically in the kidney, plays a role in the etiology of ADV nephrotoxicity by mediating its accumulation in proximal convoluted tubules. To establish a model for the evaluation of potential inhibitors of this transport process, hOAT1 was cloned and stably expressed in Chinese hamster ovary cells (CHO). The resulting CHOhOAT cells accumulated ADV to levels >50-fold higher than control CHOpIRES cells transfected with the empty expression vector. Consequently, CHOhOAT cells showed significantly higher susceptibility to ADV cytotoxicity than the control cells. Among a variety of tested compounds, NSAIDs were identified as highly effective inhibitors of ADV transport via hOAT1 Ketoprofen, naproxen, indomethacin, and ibuprofen were equally or more effective (IC50 values ranging from 1.5 to 10 µM) than probenecid, a known potent inhibitor of hOATl (IC50 = 8 µM) with in vivo nephroprotective effects. In the absence of ADV, the majority of tested NSAIDs did not show a significant increase in cytotoxicity upon hOAT1 expression, suggesting that despite their strong inhibitory properties, they may not be efficiently transported by hOAT1. Importantly, NSAIDs significantly reduced the cytotoxicity of ADV in CHOhOAT cells, but not in control CHOpIRES cells. In the presence of 100 µM ketoprofen or naproxen, the cytotoxicity of ADV in CHOhOAT decreased 6- to 10-fold compared to a 3-fold decrease in the presence of 100 µM probenecid. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of nephrotoxicity in AIDS patients on ADV therapy. Key Words: ADEFOVIR, NEPHROTOXICITY, NSAIDs |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |