Effects of ethanol on cocaine metabolism: Formation of cocaethylene and norcocaethylene

Dean, Robert A.; Harper, Edwin T.; Dumaual, Natividad; Stoeckel, David; Bosron, William F.

doi:10.1016/0041-008x(92)90210-j

Cited by 111 publications

(48 citation statements)

References 22 publications

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“…However, studies have shown that in both dogs and humans the two major metabolites of cocaine are benzoylecgonine and ecgonine methyl ester and that ethanol inhibits the elimination of cocaine (Dean et al, 1991(Dean et al, , 1992Boyer and Petersen, 1992;Roberts et al, 1993;Parker et al, 1996). In addition, in vitro formation of cocaethylene from cocaine and ethanol has been demonstrated in dog hepatic microsomal preparations (Song et al, 1999).…”

Section: Laizure Et Almentioning

confidence: 99%

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

Laizure¹,

Mandrell²,

Gades³

et al. 2003

Drug Metabolism and Disposition

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ABSTRACT: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 sam- Most cocaine users also ingest ethanol (McCance-Katz et al., 1993). This combination results in a decrease in the clearance of cocaine and the formation of the pharmacologically active metabolite, cocaethylene (Perez-Reyes et al., 1994;Hart et al., 2000). These alterations in the metabolic disposition of cocaine are mediated through the effects of ethanol on carboxylesterase. In humans, two carboxylesterase enzymes have been identified, carboxylesterase 1 (hCE1 1 ) and carboxylesterase 2 (hCE2) that participate in the metabolism of cocaine (Dean et. al., 1991;Brzezinski et. al., 1997). Although present in many tissues including heart, stomach, kidney, colon, and others, they are most abundant in the liver (Riddles et al., 1991;Schwer et al., 1997). Carboxylesterases are located in the endoplasmic reticulum and catalyze the hydrolysis of lipophilic esters to their more water-soluble alcohol and acyl substituents. There is evidence for the involvement of carboxylesterases in the metabolism of endogenous substrates such as lipids and steroids, but their primary function seems to be protecting the body from foreign substances encountered through the diet and other routes (Satoh et al., 2002). The carboxylesterases hCE1 and hCE2 are low affinity, high capacity enzymes able to hydrolyze a wide variety of structurally dissimilar esters (Kroetz et al., 1993;Satoh et al., 2002).Perhaps the best-known and most thoroughly studied substrate of hCE1 and hCE2 is cocaine. Cocaine is primarily eliminated by hydrolysis to benzoylecgonine by hCE1 and to ecgonine methyl ester by hCE2 with subsequent renal elimination. When ethanol is consumed with cocaine, a new metabolite is produced, cocaethylene (Rafla and Epstein, 1979;Boyer and Petersen, 1992;Bourland et al., 1997). Its formation results from hCE1 catalyzed transesterification between cocaine and ethanol as opposed to the normal reaction with water (hydrolysis) that produces the inactive metabolite, benzoylecgonine (Dean et al., 1991;Boyer and Petersen, 1992;Brzezinski et al., 1994;Bourland et al., 1997). Structurally, cocaine and cocaethylene differ only in the substitution of ethyl in place of the methyl ester [i.e., the ecgonine methyl ester (cocaine) is metabolized to ethyl ester (cocaethylene)]. Because of the...

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Section: Laizure Et Almentioning

confidence: 99%

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

Laizure¹,

Mandrell²,

Gades³

et al. 2003

Drug Metabolism and Disposition

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“…1, cocaine is eliminated primarily by hydrolysis to benzoylecgonine (BE) and ecgonine methyl ester (EME) by CES1 and CES2 (Dean et al, 1991;Brzezinski et al, 1994;Pindel et al, 1997;Laizure et al, 2003). Ethanol has been demonstrated in vitro to inhibit both carboxylesterases (Roberts et al, 1993) and in animals and humans to inhibit the hydrolysis of cocaine to BE by CES1 (Dean et al, 1992;McCance-Katz et al, 1993;Henning et al, 1994). However, the primary focus of previous studies has been characterizing the pharmacokinetic and pharmacodynamic interaction as it relates to the abuse of cocaine and ethanol; thus, cocaine was usually administered by nonoral routes (intravenous, intraperitoneal, smoking, and insufflation).…”

mentioning

confidence: 99%

The Effect of Ethanol on Oral Cocaine Pharmacokinetics Reveals an Unrecognized Class of Ethanol-Mediated Drug Interactions

Parker

Laizure

2010

Drug Metabolism and Disposition

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ABSTRACT: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.

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“…Vaccination with the dAd5GNE vaccine evoked antibodies with high specificity for cocaine and the active metabolite, cocaethylene (physiological byproduct from the covalent interaction of cocaine and alcohol), and with lower specificity for the active metabolite, norcocaine (Fig. 1B) (Dean et al, 1992;Brzezinski et al, 1997;Allen, 2011). The anticocaine antibodies showed lower specificity for the nonactive metabolites, benzoylecgonine and ecgonine methyl ester, and much lower binding affinity for procaine, a low affinity control.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its profound effects on the brain and the heart, cocaine also has significant effects on peripheral organs, altering metabolism in the blood vessels, adrenal glands, and kidneys within minutes of cocaine administration (Benowitz, 1993;Blake et al, 1994;Mendelson et al, 2003). In these organs, butylcholinesterase and hydrolases enzymatically degrade the cocaine molecule (Barnett et al, 1981;Jeffcoat et al, 1989;Dean et al, 1992;Brzezinski et al, 1997;Gorelick, 1997), and these cocaine degradation products are potentially toxic in the organs in which they accumulate (Kloss et al, 1983;Silva et al, 1991;Lipton et al, 2000).…”

Section: Cocaine Metabolismmentioning

confidence: 99%

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

Hicks

Kaminsky

et al. 2014

Human Gene Therapy Clinical Development

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Cocaine use disorders are mediated by the cocaine blockade of the dopamine transporter in the central nervous system (CNS). On the basis of the concept that these effects could be obviated if cocaine were prevented from reaching its cognate receptors in the CNS, we have developed an anticocaine vaccine, dAd5GNE, based on a cocaine analog covalently linked to capsid proteins of an E1 -E3 -serotype 5 adenovirus. While the vaccine effectively blocks systemically administered cocaine from reaching the brain by mediating sequestration of the cocaine in the blood, the fact that cocaine also has significant peripheral effects raises concerns that vaccinationmediated redistribution could lead to adverse effects in the visceral organs. The distribution of systemically administered cocaine at a weight-adjusted typical human dose was evaluated along with cocaine metabolites in both dAd5GNE-vaccinated and control nonhuman primates. dAd5GNE sequestration of cocaine to the blood not only prevented cocaine access to the CNS, but also limited access of both the drug and its metabolites to other cocaine-sensitive organs. The levels of cocaine in the blood of vaccinated animals rapidly decreased, suggesting that while the antibody limits access of the drug and its active metabolites to the brain and sensitive organs of the periphery, it does not prolong drug levels in the blood compartment. Gross and histopathology of major organs found no vaccine-mediated untoward effects. These results build on our earlier measures of efficacy and demonstrate that the dAd5GNE vaccine-mediated redistribution of administered cocaine is not likely to impact the vaccine safety profile.

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Effects of ethanol on cocaine metabolism: Formation of cocaethylene and norcocaethylene

Cited by 111 publications

References 22 publications

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases

The Effect of Ethanol on Oral Cocaine Pharmacokinetics Reveals an Unrecognized Class of Ethanol-Mediated Drug Interactions

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

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