College of Pharmacy, Department of Clinical Pharmacy, University of Tennessee, 910 Madison Ave., Memphis, TN 38163, USA.
Drug Metab Dispos. 2010 Feb;38(2):317-22. doi: 10.1124/dmd.109.030056. Epub 2009 Nov 17.
Ethanol decreases the clearance of cocaine by inhibiting the hydrolysis of cocaine to benzoylecgonine and ecgonine methyl ester by carboxylesterases, and there is a large body of literature describing this interaction as it relates to the abuse of cocaine. In this study, we describe the effect of intravenous ethanol on the pharmacokinetics of cocaine after intravenous and oral administration in the dog. The intent is to determine the effect ethanol has on metabolic hydrolysis using cocaine metabolism as a surrogate marker of carboxylesterase activity. Five dogs were administered intravenous cocaine alone, intravenous cocaine after ethanol, oral cocaine alone, and oral cocaine after ethanol on separate study days. Cocaine, benzoylecgonine, and cocaethylene concentrations were determined by high-performance liquid chromatography. Cocaine had poor systemic bioavailability with an area under the plasma concentration-time curve that was approximately 4-fold higher after intravenous than after oral administration. The coadministration of ethanol and cocaine resulted in a 23% decrease in the clearance of intravenous cocaine and a 300% increase in the bioavailability of oral cocaine. Cocaine behaves as a high extraction drug, which undergoes first-pass metabolism in the intestines and liver that is profoundly inhibited by ethanol. We infer from these results that ethanol could inhibit the hydrolysis of other drug compounds subject to hydrolysis by carboxylesterases. Indeed, there are numerous commonly prescribed drugs with significant carboxylesterase-mediated metabolism such as enalapril, lovastatin, irinotecan, clopidogrel, prasugrel, methylphenidate, meperidine, and oseltamivir that may interact with ethanol. The clinical significance of the interaction of ethanol with specific drugs subject to carboxylesterase hydrolysis is not well recognized and has not been adequately studied.
乙醇通过抑制羧酸酯酶对可卡因的水解，降低可卡因的清除率，生成苯甲酰古柯碱和可可碱甲酯，有大量文献描述了这种相互作用与可卡因滥用的关系。在这项研究中，我们描述了静脉内给予乙醇对犬静脉内和口服给予可卡因后的药代动力学的影响。目的是确定乙醇对代谢水解的影响，将可卡因代谢作为羧酸酯酶活性的替代标志物。在不同的研究日，5 只狗分别接受了单独静脉内给予可卡因、静脉内给予可卡因后给予乙醇、单独口服给予可卡因和口服给予可卡因后给予乙醇。通过高效液相色谱法测定可卡因、苯甲酰古柯碱和古柯烯的浓度。可卡因的全身生物利用度较差，静脉内给予后的曲线下血浆浓度-时间曲线面积约为口服给予后的 4 倍。乙醇和可卡因的联合给予导致静脉内给予可卡因的清除率降低 23%，口服给予可卡因的生物利用度增加 300%。可卡因表现为高提取药物，在肠道和肝脏中经历首过代谢，乙醇可显著抑制其代谢。我们从这些结果推断，乙醇可能抑制其他受羧酸酯酶水解的药物化合物的水解。事实上，有许多常用的处方药具有显著的羧酸酯酶介导的代谢，如依那普利、洛伐他汀、伊立替康、氯吡格雷、普拉格雷、哌甲酯、哌替啶和奥司他韦，它们可能与乙醇相互作用。乙醇与受羧酸酯酶水解影响的特定药物相互作用的临床意义尚未得到充分认识，也未得到充分研究。
