Lu K, McLean M A, Vestal M L, Newman R A
Department of Experimental Pediatrics, University of Houston, TX.
Cancer Chemother Pharmacol. 1988;21(2):134-8. doi: 10.1007/BF00257359.
Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m2) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t1/2 of Amonafide was 2.4 +/- 0.4 min, the intermediate t1/2, 26.8 +/- 3.7 min, and the terminal t1/2, 21.7 +/- 4.0 h. The peak plasma concentration achieved was 6.3 +/- 1.7 micrograms/ml. The average apparent volume of distribution was 12.84 +/- 0.54 1/kg, and the total clearance was 0.56 +/- 0.16 1/kg/h. In 24 h, 9.5% +/- 0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4% +/- 1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20-25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The alpha and beta plasma t1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.
氨萘非特是布拉纳等人合成的一系列1,8-萘二甲酸酰亚胺衍生物之一，已显示出对多种实验性肿瘤具有显著的抗肿瘤活性，包括L1210白血病和P388白血病。在我们研究所进行临床试验的同时，我们通过高效液相色谱法和荧光测定法研究了氨萘非特在犬体内的处置情况。6只犬静脉注射氨萘非特，剂量为5mg/kg（100mg/m²），持续15分钟；3只在6小时后处死，3只在24小时后处死。氨萘非特的初始血浆半衰期为2.4±0.4分钟，中间半衰期为26.8±3.7分钟，终末半衰期为21.7±4.0小时。达到的血浆峰值浓度为6.3±1.7μg/ml。平均表观分布容积为12.84±0.54l/kg，总清除率为0.56±0.16l/kg/h。在24小时内，给药剂量的9.5%±0.2%以原形药物形式经尿液排泄，7.4%±1.4%在6小时内经胆汁排泄。氨萘非特很容易穿透脑脊液，给药后20 - 25分钟达到最高浓度，为同时期血浆水平的30%。氨萘非特经历广泛代谢，产生至少三种主要代谢产物和两种或更多种次要代谢产物。主要代谢产物N-氧化物衍生物的α和β血浆半衰期分别为24.8分钟和28.6小时。24小时累积尿排泄量为注射剂量的1.4%，6小时累积胆汁排泄量为16.7%。给药6小时后尸检发现，肝脏中未变化的氨萘非特含量百分比最高（为给药剂量的0.23%），其次是胃（0.11%）、肺（0.04%）、肾（0.04%）和胰腺（0.03%）。其余主要器官中氨萘非特的含量低于给药剂量的0.02%。给药一天后，在这些组织中均未检测到氨萘非特，这表明氨萘非特在犬体内似乎被广泛代谢，且未大量潴留。
