Metabolism cocaine

R. A. Dean, E. T. Harper, N. Dumaual, D. A. Stoeckel, W. F. Bosron, Effects of Ethanol on Cocaine Metabolism Formation of Cocaethylene and Norcocaethylene , Toxicol. Appl. Pharmacol. 1992,117, 1-8. 

Zhang, J.Y. and Foltz, R.L., Cocaine metabolism in man identification of four previously unreported cocaine metabolites in human urine, J. Anal. Toxicol., 14, 201-205, 1990. 

Cone, E.J. et al., Cocaine metabolism and urinary excretion after different routes of administration, Ther. Drug Monit., 20, 556-560, 1998. 

Cartmell, L. W., Aufderhide, A., and Weems, C., Cocaine metabolism in pre-Columbian mummy hair,. Okla. State Med. Assoc., 84, 11, 1991. 

The blocking action could also be implemented by administration of an enzyme or a catalytic antibody (regarded as an artificial enzyme) that not only binds but also accelerates cocaine metabolism and thereby frees itself for further binding [16-25]. Usually, a pharmacokinetic agent would not be expected to across the blood-brain barrier and thus would itself have no direct pharmacodynamic action, such as abuse liability [5]. 

Ethanol is frequently consumed with other recreational drugs. Cocaine abuse has resulted in an increase of catastrophic cardiovascular events such as myocardial infarction, ventricular arrhythmias, angina pectoris, and sudden death. Many of those so affected also consume ethanol prior to cocaine use. The drug combination of ethanol first followed by cocaine use has been shown to generate synergistic cardiovascular effects in humans and animalsJ24-27 The findings are believed to be due to the inhibition effect of ethanol on cocaine metabolism. 281... 

Dean RA, Harper ET, Dumaual N, et al. Effects of ethanol on cocaine metabolism Formation of cocaethylene and norcoethylene. ToxicolApplPharmacol 1992 117 (1) 18. 

Cocaine Metabolism. Because cocaine (3)has two ester functions, both can be hydrolyzed in vivo to generate metabolites. Hydrolysis of the methyl ester leads to benzo-ylecgonine (12), and hydrolysis of the benzoyl ester leads to ecgonine methyl ester (13).Tro-pan-3j3-ol-2j8-carboxylic acid is known as ecgonine (14). In cocaine users who also consume significant amounts of ethanol, a transesterification product (cocaethylene, 15) is also detected. Cocaethylene is also a potent psychostimulant, with about four times higher potency as a local anesthetic than that of cocaine itself (69), and can enhance the cardio-toxicity associated with cocaine use. 

Hence, the duration and magnitude of the desired stimulant effects, as well as the undesired toxic effects of cocaine use, appear to depend on the content and activity of enzymes responsible for cocaine metabolism. 

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) ... 

Stewart, D.J. Inaba, T. Eucassen, M. and Kalow, W. Cocaine metabolism Cocaine and norcocaine hydrolysis by liver and serum esterases. Clin Pharmacol Ther 25 464-468, 1979. 

Thompson, M L. Shuster, L. and Shaw, K. Cocaine-induced hepatic necrosis in mice—The role of cocaine metabolism. Biochem Pharmacol 28 2389-2395, 1979. 

As another minor point, the use of catalytic antibodies with esterase activity could theoretically lead to autoimmunity against endogenous enzymes. This problem could be partially overcome if Fab fragments were used, or perhaps completely overcome if humanized antibodies or their fragments w ere used. Also, it is not currently known if endogenous ligands will be substrates for these catalytic enzymes this could potentially decrease the effective rate for cocaine metabolism or lead to other medical problems. 

Cocaine metabolizes in the body to several compounds. The NIDA drug confirmation is based on the metabolite, benzoylecgonine. Benzoylecgonine is an amphoteric compound (contains both an amine and a carboxylic acid) that will isolate by mixed-mode SPE (Fig. 8.6). 

Bencharit, S., Morton, G. L., Xue, Y, Potter, P. M., Redinbo, M. (2003). Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nature Structural... 

Cone, E. J., A. Tsadik, J. Oyler, and W. D. Darwin. 1998. Cocaine metabolism and urinary exeretion after different routes of administration. Therap. DrugMonit. 20 556-560... 

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