在雄性小鼠体内对作为毒性最强的可卡因代谢物的去甲可乐宁和去甲古柯碱的毒性进行了表征。
In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice.
机构信息
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
出版信息
Drug Alcohol Depend. 2019 Nov 1;204:107462. doi: 10.1016/j.drugalcdep.2019.04.033. Epub 2019 Aug 30.
BACKGROUND
Majority of cocaine users also consume alcohol, and concurrent use of cocaine and alcohol produces cocaethylene, norcocaine, norcocaethylene, and other non-toxic metabolites. It is essential to know their relative toxicity for development of a truly effective therapeutics for cocaine toxicity treatment.
METHODS
Drug (norcocaethylene or norcocaine)-induced acute toxicity was characterized by the occurrence (and the timing) of prostration, seizure, and death after intraperitoneal administration of the drug (n = 15) using the same strain (Swiss Webster) of male mice reported in previous study by Hearn et al. to determine LD of cocaine and cocaethylene. In addition, drug (cocaine, cocaethylene, norcocaine, or norcocaethylene)-induced hyperactivity was determined by locomotor activity testing (n = 8).
RESULTS
According to the animal data, norcocaethylene (LD=∼39.4 mg/kg) and norcocaine (LD=∼49.7 mg/kg) are the most toxic metabolites, but they do not induce significant hyperactivity. In addition, the relative toxicity of drugs correlates with the time to the occurrence of prostration/seizure/death after the drug administration.
CONCLUSIONS
The relative toxicity of these toxic drugs can be ranked in this order: norcocaethylene > norcocaine > cocaethylene > cocaine. The data suggest that norcocaethylene, norcocaine, and cocaethylene are all significant contributors to acute toxicity of cocaine in concurrent use of cocaine and alcohol. Hence, future therapeutic development for cocaine toxicity treatment must account for detoxification of these more toxic metabolites. In addition, the relative toxicity of different drugs correlates with the average time to the occurrence of death, seizure, or prostration after the drug administration with a same dose close to their LD values.
背景
大多数可卡因使用者也会饮酒，而可卡因和酒精的同时使用会产生可乐因、去甲可乐因、去甲可乐因乙酯和其他无毒代谢物。了解它们的相对毒性对于开发真正有效的可卡因毒性治疗方法至关重要。
方法
使用与 Hearn 等人之前报道的相同的雄性瑞士 Webster 小鼠（n=15），通过腹腔内给予药物（去甲可乐因乙酯或去甲可乐因）来确定可卡因和可乐因乙酯的 LD，以研究药物（去甲可乐因乙酯或去甲可乐因）引起的急性毒性。此外，通过运动活动测试（n=8）确定药物（可卡因、可乐因乙酯、去甲可乐因或去甲可乐因乙酯）引起的过度活跃。
结果
根据动物数据，去甲可乐因乙酯（LD=∼39.4mg/kg）和去甲可乐因（LD=∼49.7mg/kg）是毒性最大的代谢物，但它们不会引起明显的过度活跃。此外，药物的相对毒性与给药后出现虚弱/抽搐/死亡的时间有关。
结论
这些有毒药物的相对毒性可以按以下顺序排列：去甲可乐因乙酯＞去甲可乐因＞可乐因乙酯＞可卡因。数据表明，去甲可乐因乙酯、去甲可乐因和可乐因乙酯都是可卡因和酒精同时使用时可卡因急性毒性的重要贡献者。因此，未来可卡因毒性治疗的治疗方法必须考虑到这些更有毒代谢物的解毒。此外，不同药物的相对毒性与给予相同接近 LD 值的剂量后死亡、抽搐或虚弱发生的平均时间相关。
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