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.
J Pharm Biomed Anal. 2024 Nov 15;250:116408. doi: 10.1016/j.jpba.2024.116408. Epub 2024 Aug 8.
Concurrent use of heroin and cocaine (known as the "speedball") prevails among substance use disorder populations, especially in opioid-dependent individuals, with severe consequences and a high fatality rate. Little is known about the patterns and correlations of the concurrent use of heroin and cocaine. It is vital to investigate such a polydrug use in both humans and animals to uncover concomitant toxicity and the cause of fatal overdose (death). In this study, we aimed to shed some light on the role of cocaine in the etiology of heroin-related deaths in the context of molecular pharmacokinetics (PK). For the purpose, a high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of heroin, cocaine, and their metabolites in whole blood was developed and fully validated in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Then, this method was used to analyze heroin, cocaine, and their metabolites in blood from the rats intraperitoneally administered non-lethal 10 mg/kg heroin or 20 mg/kg cocaine alone, or their combination that is lethal with a proximal mortality of 33 %. The obtained results from the rats that experienced the lethal toxicity revealed that the concurrent use of heroin and cocaine significantly increased the risk of fatality from overdose. Heroin significantly slowed down the elimination of cocaine and its main metabolites in blood, while cocaine significantly enhanced heroin metabolism from 6-monoacetylmorphine (6-MAM) to morphine. Similar elimination half-lives for other heroin metabolites were observed. These findings are reported for the first time in this study, facilitating our understanding of the polysubstance metabolism and severe consequences produced by the polydrug use.
海洛因和可卡因（俗称“冰毒丸”）同时使用在药物滥用人群中很常见，尤其是在阿片类药物依赖者中，会产生严重后果和高死亡率。目前对于海洛因和可卡因同时使用的模式和相关性知之甚少。了解人类和动物中这种多药物的使用情况对于揭示同时存在的毒性和致命过量（死亡）的原因至关重要。在这项研究中，我们旨在从分子药代动力学（PK）的角度探讨可卡因在海洛因相关死亡病因中的作用。为此，我们开发了一种高效液相色谱-串联质谱（LC-MS/MS）方法，用于同时测定全血中海洛因、可卡因及其代谢物，并按照美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）的指南进行了全面验证。然后，该方法用于分析腹腔注射非致死性 10mg/kg 海洛因或 20mg/kg 可卡因或其致死性组合的大鼠血液中的海洛因、可卡因及其代谢物，其近死亡率为 33%。从经历致死毒性的大鼠中获得的结果表明，海洛因和可卡因同时使用显著增加了过量致死的风险。海洛因显著减缓了可卡因及其主要代谢物在血液中的消除，而可卡因则显著增强了从 6-单乙酰吗啡（6-MAM）到吗啡的海洛因代谢。其他海洛因代谢物的消除半衰期也相似。这些发现是首次在本研究中报道的，有助于我们了解多物质代谢和多药物使用产生的严重后果。
