Dalgaard L, Hjortkjaer R K, Regnier B, Nordholm L
Pharmacokinetics Division, Novo Nordisk A/S, Denmark.
Drug Metab Dispos. 1994 Mar-Apr;22(2):289-93.
NBQX [6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione] has proven effective in protecting against cerebral ischemic insult in rodents. The preclinical development included pharmacokinetic and toxicological investigations in mice, rats, and dogs. For these purposes, NBQX was given as an intravenous bolus dose (in mice, rats, and dogs) or as a constant infusion for up to 4 weeks in rats and dogs. In NMRI mice t1/2, CL, and V2 were 1-4 hr, 0.6-1 liter/kg/hr, and 1-4 liters/kg following 3, 10, or 30 mg/kg. In Wistar and Sprague-Dawley rats, the mean +/- SD values of t1/2, CL, and Vz were 0.8 +/- 0.35 hr, 3.2 +/- 1.0 liters/kg/hr, and 4.0 +/- 1.1 liters/kg, respectively. About 33 +/- 5.2% of the dose was excreted unchanged in urine. The CLR 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 proportional to the dose rate in the dose range 0.3-10 mg/kg/hr, independent of sex, and did not change during 4 weeks of infusion. CL and CLR were decreased to half their value when NBQX was administered in combination with probenecid. In beagle dogs, t1/2 and Vz were 1-3 hr and 1-3 liters/kg, respectively. The CL was determined to be 1.5 +/- 0.4 liters/kg/hr (N = 18) following 2 days of infusion (0.2-1 mg/kg/hr), but after 1 month CL had decreased significantly (p < 0.0001) to 1.0 +/- 0.1 liter/kg/hr.(ABSTRACT TRUNCATED AT 250 WORDS)
NBQX [6-硝基-7-氨磺酰基-苯并(f)喹喔啉-2,3-二酮]已被证明在保护啮齿动物免受脑缺血损伤方面有效。临床前开发包括在小鼠、大鼠和狗身上进行药代动力学和毒理学研究。为此，NBQX以静脉推注剂量（在小鼠、大鼠和狗中）给药，或在大鼠和狗中以持续输注方式给药长达4周。在NMRI小鼠中，给予3、10或30mg/kg剂量后，t1/2、CL和V2分别为1 - 4小时、0.6 - 1升/千克/小时和1 - 4升/千克。在Wistar和Sprague-Dawley大鼠中，t1/2、CL和Vz的平均值±标准差分别为0.8±0.35小时、3.2±1.0升/千克/小时和4.0±1.1升/千克。约33±5.2%的剂量以原形从尿液中排出。CLR为0.90±0.20升/千克/小时。尿液样本的pH值范围为pH 6.2至8.8，平均值为7.9±0.72。在0.3 - 10mg/kg/小时的剂量范围内，血浆浓度与剂量率成正比，与性别无关，且在输注4周期间不变。当NBQX与丙磺舒联合给药时，CL和CLR降至其值的一半。在比格犬中，t1/2和Vz分别为1 - 3小时和1 - 3升/千克。输注2天（0.2 - 1mg/kg/小时）后，CL测定为1.5±0.4升/千克/小时（N = 18），但1个月后CL显著降低（p < 0.0001）至1.0±0.1升/千克/小时。（摘要截断于250字）
