Cocaethylene metabolism and interaction with cocaine and ethanol: Role of carboxylesterases
Cocaethylene metabolism and interaction with cocaine and ethanol: Role of carboxylesterases
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DOI：
10.1124/dmd.31.1.16
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发表时间：
2003-01-01
影响因子：
3.9
通讯作者：
Parker, RB
中科院分区：
文献类型：
--
作者：
Laizure, SC;Mandrell, T;Parker, RB
羧酸酯酶在可卡因的代谢中是重要的，催化可卡因水解成其两种主要代谢物，苯甲酰芽子碱和芽子碱甲酯。在乙醇存在的情况下，一些可卡因与乙醇发生酯交换反应，而不是与水水解，产生活性代谢物古柯乙烯。可卡因的代谢命运尚不清楚，但鉴于其结构与可卡因相似，假设可卡因也会被羧酸酯酶代谢，并且在乙醇存在下其消除减少，可卡因也是如此。在不同的研究日，分别给予狗单独的可卡因、单独的可卡因乙烯、可卡因和乙醇、可卡因乙烯和乙醇以及可卡因和可卡因乙烯，并连续抽取血样。可卡因，苯甲酰芽子碱，和可卡因的血浆浓度测定高效液相色谱法。可卡因和可卡因的药代动力学分布相似，清除率分别为0.91 +/- 0.22和0.79 +/- 0.16 l/min，分布容积分别为2.6 +/- 0.82和2.7 +/- 0.47 l/kg。当给予乙醇时，可卡因和可卡因的清除率均降低约20%。单独给予可卡因后，苯甲酰基爱子宁达到的血浆浓度与单独给予可卡因后达到的浓度相似，这表明苯甲酰基爱子宁是可卡因的主要代谢物。羧酸酯酶在可卡因和可卡因乙烯的消除中起重要作用。
Carboxylesterases are important in the metabolism of cocaine, catalyzing the hydrolysis of cocaine to its two major metabolites, benzoylecgonine and ecgonine methyl ester. In the presence of ethanol, some cocaine undergoes transesterification with ethanol instead of hydrolysis with water producing the active metabolite, cocaethylene. The metabolic fate of cocaethylene is unknown, but given its structural similarity to cocaine, it was hypothesized that cocaethylene would also be metabolized by carboxylesterases and its elimination decreased in the presence of ethanol, as is cocaine's. Dogs were given cocaine alone, cocaethylene alone, cocaine and ethanol, cocaethylene and ethanol, and cocaine and cocaethylene on separate study days and sequential blood samples drawn. Plasma concentrations of cocaine, benzoylecgonine, and cocaethylene were determined by high-performance liquid chromatography. The pharmacokinetic dispositions of cocaine and cocaethylene were similar with clearance values of 0.91 +/- 0.22 and 0.79 +/- 0.16 l/min, and volumes of distribution of 2.6 +/- 0.82 and 2.7 +/- 0.47 l/kg, respectively. Both cocaine and cocaethylene clearances were decreased about 20% when given with ethanol. Following administration of cocaethylene alone, benzoylecgonine achieved similar plasma concentrations as those attained following cocaine alone, which indicates that benzoylecgonine is a major metabolite of cocaethylene. Carboxylesterases play an important role in the elimination of both cocaine and cocaethylene.