PIII‐52

BACKGROUND NXY‐059 is a novel free‐radical trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke (AIS). In an initial Phase III study (SAINT I) NXY‐059 has shown efficacy in AIS by reducing functional disability. NXY‐059 is eliminated by renal excretion, primarily through glomerular filtration but with 30% estimated as active tubular secretion. This study was designed to further characterize the active renal excretion of NXY‐059. Probenecid and cimetidine, substrates for renal systems that transport organic acids and bases, were chosen as model inhibitors. METHODS This was a single‐center, randomized, open‐label, parallel group study. 55 healthy subjects received a 12‐h iv infusion of NXY‐059 (target plasma concentrations 25–30 μmol/L) with one of these treatments given at 6h: Group A : Oral 1.5g probenecid Group B : Oral 800mg cimetidine Group C : Control Renal clearance (CL R ) of NXY‐059 was estimated before and after administration of the inhibitor. RESULTS The CL R of NXY‐059 in the probenecid group decreased by 30%, from an average of 108 mL/min (before 6h) to 75.5 mL/min (after 6h)[p<0.001]. There was no statistically significant difference in the mean CL R of NXY‐059 before and after 6h for either the cimetidine or control group. CONCLUSIONS The active tubular secretion of NXY‐059 occurs through an organic acid transporter, not an organic base transporter. This active secretion contributes approximately 30% of the renal elimination. Clinical Pharmacology & Therapeutics (2005) 79 , P72–P72; doi: 10.1016/j.clpt.2005.12.260