Pan W J, Hedaya M A
Pharmacology/Toxicology Graduate Program, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6510, USA.
J Pharm Sci. 1999 Apr;88(4):468-76. doi: 10.1021/js980283h.
The pharmacokinetics and pharmacodynamics of cocaine and its three metabolites, benzoylecgonine, norcocaine, and cocaethylene, were investigated in awake, freely moving rats. This work was performed to examine the effect of alcohol coadministration on the metabolic profile of cocaine and to determine the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular fluid concentration-time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experimental design. The neurochemical response, measured as the change in dopamine concentration in the nucleus accumbens, and the cardiovascular responses, measured as the change in the mean arterial blood pressure, heart rate, and QRS interval, were monitored simultaneously. Cocaethylene had the highest brain-to-plasma distribution ratio, followed by cocaine, norcocaine, and benzoylecgonine. The estimated total body clearances for cocaine, benzoylecgonine, norcocaine, and cocaethylene were 140 +/- 19, 14.7 +/- 1.2, 130 +/- 19, and 111 +/- 16 mL/min/kg, respectively. Alcohol coadministration increased the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite cocaethylene. When cocaine was administered with alcohol, 12.9 +/- 3.1% to 15.3 +/- 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgonine did not have any central nervous system or cardiovascular activities after iv administration. Compared with cocaine, norcocaine and cocaethylene had more potent and prolonged effects on the neurochemical, heart rate, and QRS interval responses, and were equipotent in increasing the mean arterial blood pressure. These results indicate that changes in the cocaine metabolic profile and the formation of the pharmacologically active metabolite cocaethylene are, at least partially, responsible for the more intense and longer lasting effects reported after using this drug in combination with alcohol.
在清醒、自由活动的大鼠中研究了可卡因及其三种代谢物苯甲酰爱康宁、去甲可卡因和可口卡因的药代动力学和药效学。进行这项研究是为了检验酒精共同给药对可卡因代谢谱的影响，并确定可卡因代谢物对可卡因给药后观察到的药理反应的贡献。采用交叉实验设计，静脉注射可卡因及其三种代谢物后，对血浆和脑细胞外液浓度-时间曲线进行了表征。同时监测神经化学反应（以伏隔核中多巴胺浓度的变化来衡量）和心血管反应（以平均动脉血压、心率和QRS间期的变化来衡量）。可口卡因的脑-血浆分布比最高，其次是可卡因、去甲可卡因和苯甲酰爱康宁。可卡因、苯甲酰爱康宁、去甲可卡因和可口卡因的估计全身清除率分别为140±19、14.7±1.2、130±19和111±16 mL/min/kg。酒精共同给药增加了去甲可卡因的形成，减少了苯甲酰爱康宁的形成，并导致了药理活性代谢物可口卡因的形成。当可卡因与酒精一起给药时，12.9±3.1%至15.3±2.9%的可卡因剂量转化为可口卡因。静脉注射后，苯甲酰爱康宁没有任何中枢神经系统或心血管活性。与可卡因相比，去甲可卡因和可口卡因对神经化学、心率和QRS间期反应的作用更强且持续时间更长，在升高平均动脉血压方面作用相当。这些结果表明，可卡因代谢谱的变化以及药理活性代谢物可口卡因的形成至少部分地导致了使用该药物与酒精联合使用后所报告的更强烈和更持久的效果。
