Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases.

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.