PIII-52Effects of cimetidine and probenecid on renal clearance of NXY-059, a novel neuroprotectant: A phase I study to determine the transporter responsible for active secretion

Abstract

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 (CLR) of NXY-059 was estimated before and after administration of the inhibitor. RESULTS The CLR 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 CLR 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