PHARMACOKINETICS OF THE NEUROPROTECTIVE GLUTAMATE ANTAGONIST NBQX 6-NITRO-7-SULFAMOYL-BENZO(F)QUINOXALINE-2-3-DIONE) IN MICE, RATS, AND DOGS - INTERACTIONS WITH PROBENECID

NBQX 6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione] has proven eff ective in protecting against cerebral ischemic insult in rodents. The preclinical development included pharmacokinetic and toxicological inv estigations in mice, rats, and dogs. For these purposes, NBQX was give n as an intravenous bolus dose (in mice, rats, and dogs) or as a const ant infusion for up to 4 weeks in rats and dogs. In NMRI mice t(1/2), CL, and V-2 were 1-4 hr, 0.6-1 liter/kg/hr, and 1-4 liters/kg followin g 3, 10, or 30 mg/kg. In Wistar and Sprague-Dawley rats, the mean +/- SD values of t(1/2), CL, and V-z were 0.8 +/- 0.35 hr, 3.2 +/- 1.0 lit ers/kg/hr, and 4.0 +/- 1.1 liters/kg, respectively. About 33 +/- 5.2% of the dose was excreted unchanged in urine. The CL(R) was 0.90 +/- 0. 20 liter/kg/hr. The pH of the urine samples ranged from pH 6.2 to 8.8, with a mean of 7.9 +/- 0.72. The plasma concentrations were proportio nal to the dose rate in the dose range 0.3-10 mg/kg/ hr, independent o f sex, and did not change during 4 weeks of infusion. CL and CLR were decreased to half their value when NBQX was administered in combinatio n with probenecid. In beagle dogs, t(1/2) and V-z were 1-3 hr and 1-3 liters/kg, respectively. The CL was determined to be 1.5 +/- 0.4 liter s/kg/hr (N = 18) following 2 days of infusion (0.2-1 mg/kg/hr), but af ter 1 month CL had decreased significantly (p < 0.0001) to 1.0 +/- 0.1 liter/kg/hr. At higher dose rates (3-5 mg/kg/hr), which could only be maintained for < 4 hr, the clearance was 0.7-1 liter/kg/hr, indicatin g nonlinear kinetics.