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Vol. 295, Issue 1, 10-15, October 2000
Gilead Sciences, Foster City, California
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
(IC50 = 0.85-8 µM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC50 = 8 and 6 µM, 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
[3H]ketoprofen and [3H]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.
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