Borzelleca J F, Egle J L, Harris L S, Belleville J A
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
J Appl Toxicol. 1995 Sep-Oct;15(5):339-55. doi: 10.1002/jat.2550150503.
This study evaluated levo-alpha-noracetylmethadol (NorLAAM), the first N-demethylated metabolite of levo-alpha-acetylmethadol (LAAM), a long-acting morphine-like (mu) agonist, approved in 1993 to treat opiate dependence. After acute and 7-day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague-Dawley rats (20 of each sex per group) were gavaged with doses of 4.4-25.9 mg kg(-1) day(-1) for 30 days followed by a 14-day recovery period. Treatment-related effects included dose-dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage-biting and gnawing behavior were observed only with NorLAAM. Mortality was dose-dependent, with deaths occurring predominantly during the first week. At day 30, all male-treated groups exhibited statistically significant, dose-dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid- and high-dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid- and high-dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primary N-demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a mu-agonist, which stimulates hepatic microsomal enzymes in rodents.
本研究评估了左-α-去甲乙酰美沙多（NorLAAM），它是长效吗啡样（μ）激动剂左-α-乙酰美沙多（LAAM）的首个N-去甲基代谢物，于1993年被批准用于治疗阿片类药物依赖。在进行急性和为期7天的预试验以确定适用于长期评估的剂量水平后，对每组20只（雌雄各半）的Sprague-Dawley大鼠每天灌胃给予4.4 - 25.9毫克/千克的剂量，持续30天，随后有14天的恢复期。与治疗相关的效应包括剂量依赖性的中枢神经系统抑制，同时伴有食物摄入量、体重增加和粪便排出量的变化，以及尿液呈红色和腹部染色。在第7天时产生了耐受性。观察到的活性谱与母体化合物的主要差异在于其时间进程。仅在给予NorLAAM时观察到咬笼和啃咬行为。死亡率呈剂量依赖性，主要在第一周内发生死亡。在第30天时，所有接受治疗的雄性组体重增加均出现统计学上显著的剂量依赖性下降，血清胆固醇升高，恢复后回到对照范围。脑/体重和睾丸/体重比值增加，肾/脑、肝/脑、脾/脑和心/脑比值下降，以及肾、肝、脾和心脏绝对重量下降，仅在雄性中具有统计学意义。在处死时，肾脏的组织学检查结果显示，中、高剂量组的两性肾小管矿物质沉积发生率增加，雌性的皮质髓质矿物质沉积增加。雄性和雌性中、高剂量组均出现明显的肝小叶中央肥大。恢复期后组织病理学变化减轻。总之，急性和重复给予NorLAAM产生的药效学特征与其作为LAAM主要N-去甲基代谢物的作用相符，它比母体化合物更具活性且亲脂性更低；这反映在观察到的毒理学结果中。与LAAM一样，NorLAAM的总体活性模式与其作为μ-激动剂的活性一致，它能刺激啮齿动物的肝微粒体酶。
