Benzoylecgonine ethyl ester

There is an additional factor contributing to the toxicity of cocaine, namely its interaction with ethanol [122] [123], Many cocaine (ab)users simultaneously ingest ethanol, probably to experience potentiation of effects and attenuation of headaches. It is now known that ethanol interferes in two ways with the metabolism of cocaine, first by inhibiting its hydrolysis and second by allowing transesterification to form benzoylecgonine ethyl ester (7.61, Fig. 7.8) commonly known as cocaethylene. These metabolic effects are illustrated by studies in the rat (Table 7.3), with ethanol inhibiting the formation of... 

Fig. 7.9. Mechanism of carboxylesterase-catalyzed transesterification of cocaine to cocaethylene, schematized in analogy to Fig. 3.3,d-f (Chapt. 3). Ethanol enters the catalytic cycle at Step d and reacts with the benzoylecgoninyl moiety (Steps < and / ) to form benzoylecgonine ethyl ester [125].

It, thus, appears that the capacity to catalyze reactions of transesterification and esterification is a characteristic of various hydrolases (Chapt. 3). Apart from the carboxylesterases discussed here, lipoprotein lipase has the capacity to synthesize fatty acid ethyl esters from ethanol and triglycerides, or even fatty acids [127]. Ethanol, 2-chloroethanol, and other primary alcohols serve to esterify endogenous fatty acids and a number of xenobiotic acids [128-130]. In this context, it is interesting to note that the same human liver carboxylesterase was able to catalyze the hydrolysis of cocaine to benzoylecgonine, the transesterification of cocaine, and the ethyl esterification of fatty acids [131]. 

Once in the blood stream, cocaine levels quickly rise in the brain, faster than plasma levels, which then redistribute to other tissues. Cocaine is rapidly metabolized in the blood and liver, with a half-life of 30 to 90 minutes. The major metabolites have a half-life of approximately 8 hours. Although cocaine itself is detected in urine for only 12 hours, the metabolite benzoylecgonine can be detected in urine for at least 48 hours and sometimes up to 2 weeks. Concurrent use of cocaine and ethanol produces an ethyl ester of benzoylecgonine called cocaethylene. Cocaethylene is an active metabolite, blocking dopamine reuptake, and potentiating the effect of cocaine. Thus, concurrent use of cocaine and ethanol can further increase the additional effects of the drugs and the risk of dependency. 

EME and BEG, which is mainly obtained by enzymatic hydrolysis, represents respectively the 32-49 % and 29 45 % of total urinary metabolites cocaine can be converted, in small amounts, to norcocaine (NCOC) and psychoactive metabolite norbenzoylecgonine (NBE). The combined intake of alcohol and cocaine determines the formation of a pharmacologically active metabolite, the cocaethylene (ethyl ester of benzoylecgonine, CE), with a significant liver toxicity [13],... 

Fig. 1. Chromatography of cocaine and related analytes. A 5 ng/mL standard containing all analytes and internal standards is shown. Anhydroecgonine ethyl ester (AEEE) is shown but not described in the above method because the pure compound is not commercially available. AEME anhydroecgonine methyl ester, 8E benzoylecgonine, CE cocaethylene, COC cocaine, /77-HOBE /77-hydroxybenzoylecgonine, /VC norcocaine.

Cocaine metabolism and disposition following acute ethanol administration were studied in the rat to determine if the in vitro effects of ethanol on cocaine methyl esterase and ethyl transferase activities had significance in vivo (Zachman et al. 1993). The rat was used as it possesses both ethyl transferase and methyl esterase activities, is frequently employed for behavioral and toxicity studies of cocaine, and the size provides sufficient tissue for anal 4 ical work. This study was designed to address three questions. First, do significant concentrations of cocaethylene form and accumulate in tissues with controlled coadministrations of cocaine and alcohol Second, does ethanol administration significantly diminish the hydrolysis of cocaine to benzoylecgonine and methanol, as occurs in vitro when cocaine and ethanol are coincubated with purified human liver carboxylesterase (Brzezinski et al. 1994 Dean et al. 1991) Third, does ethanol inhibition of cocaine methyl ester hydrolysis increase the N-oxidative metabolism of cocaine, as noted when rodents are pretreated with nonspecific esterase inhibitors (Thompson etal. 1979) ... 

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