Cocaine Metabolism in Humans after Use of Alcohol Clinical and Research Implications

Camı́, Jordi; Farré, Magı́; González, María Luisa Gómez; Segura, Jordi; Torre, Rafael de la

doi:10.1007/0-306-47148-5_22

Cited by 49 publications

(31 citation statements)

References 59 publications

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“…Alcohol has been shown to inhibit cocaine hydrolysis catalyzed by CES1 and CES2 (Roberts et al, 1993;Song et al, 1999) and the hydrolysis of methylphenidate (Bourland et al, 1997) and clopidogrel (Tang et al, 2006) (all by CES1) in microsomes or HLS9 fractions. In human studies, cocaine and methylphenidate hydrolysis are significantly inhibited by the consumption of alcohol and the transesterification products cocaethylene and ethylphenidate are produced (Farre et al, 1997;Cami et al, 1998;Patrick et al, 2007). These studies show that the inhibition of carboxylesterase hydrolysis and the formation of transesterified metabolites are not unique to the cocaine-alcohol interaction and may occur with other CES1 substrates.…”

Section: Discussionmentioning

confidence: 99%

“…One such factor is drug interactions that inhibit carboxylesterase function (Parker and Laizure, 2010;Zhu et al, 2010;Rhoades et al, 2012). It is well established that alcohol is an inhibitor of carboxylesterase-mediated cocaine hydrolysis (Farre et al, 1997;Cami et al, 1998;Song et al, 1999;Laizure et al, 2003;Parker and Laizure, 2010). Whether this effect of alcohol is specific for cocaine or is more broadly applicable to other CES1 substrates is uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

et al. 2013

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Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted to the active thrombin inhibitor, dabigatran (DAB), by serine esterases. The aims of the present study were to investigate the in vitro kinetics and pathway of DABE hydrolysis by human carboxylesterase enzymes, and the effect of alcohol on these transformations. The kinetics of DABE hydrolysis in two human recombinant carboxylesterase enzymes (CES1 and CES2) and in human intestinal microsomes and human liver S9 fractions were determined. The effects of alcohol (a known CES1 inhibitor) on the formation of DABE metabolites in carboxylesterase enzymes and human liver S9 fractions were also examined. The inhibitory effect of bis(4-nitrophenyl) phosphate on the carboxylesterase-mediated metabolism of DABE and the effect of alcohol on the hydrolysis of a classic carboxylesterase substrate (cocaine) were studied to validate the in vitro model. The ethyl ester of DABE was hydrolyzed exclusively by CES1 to M1 (K m 24.9 6 2.9 mM, V max 676 6 26 pmol/min per milligram protein) and the carbamate ester of DABE was exclusively hydrolyzed by CES2 to M2 (K m 5.5 6 0.8 mM; V max 71.1 6 2.4 pmol/min per milligram protein). Sequential hydrolysis of DABE in human intestinal microsomes followed by hydrolysis in human liver S9 fractions resulted in complete conversion to DAB. These results suggest that after oral administration of DABE to humans, DABE is hydrolyzed by intestinal CES2 to the intermediate M2 metabolite followed by hydrolysis of M2 to DAB in the liver by CES1. Carboxylesterase-mediated hydrolysis of DABE was not inhibited by alcohol.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

et al. 2013

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“…1) by CES1 and CES2 (Isenschmid et al, 1992;Dean et al, 1995;Kamendulis et al, 1996;Cone et al, 1998), and it is one of the few carboxylesterase substrates whose interaction with ethanol has been studied extensively. Studies of the effect of ethanol on cocaine pharmacokinetics have focused on the pharmacodynamic interaction in drug abuse and have reported on administration of cocaine by the intravenous, intraperitoneal, nasal, and smoking routes (Farré et al, 1993;Cami et al, 1998;Laizure et al, 2003). All of these routes of administration bypass the first-pass metabolism of cocaine either completely (intravenous and smoking) or partially (intraperitoneal and intranasal).…”

Section: Discussionmentioning

confidence: 99%

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

Parker

Laizure

2009

Drug Metab Dispos

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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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“…Commonly, the use of one substance leads to the use of the other (Dackis & O'Brien, 2001;Heil et al, 2001;Mengis et al, 2002). Additionally, concurrent use of cocaine and alcohol notably yields cocaethylene (McCance-Katz et al, 1993), an active transesterified metabolite associated with more lethality (Andrews, 1997;Jatlow et al, 1991;Katz, Terry, & Witkin, 1992) and toxicity (Cami, Farre, Gonzalez, Segura, & de la Torre, 1998;McCance-Katz, Kosten, & Jatlow, 1998;Pennings, Leccese, & Wolff, 2002;Wilson, Jeromin, Garvey, & Dorbandt, 2001) than cocaine alone. Postmortem studies link lethal overdose with cocaethylene (Jatlow et al, 1991), which has been estimated to increase the risk of sudden death by 18-25 fold when compared to cocaine alone (Andrews, 1997).…”

Section: Introductionmentioning

confidence: 99%

Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence

Pettinati

Kampman

Lynch

et al. 2008

Journal of Substance Abuse Treatment

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This is a randomized, double blind, placebo-controlled clinical trial that evaluated the efficacy of a higher than typical daily dose of naltrexone (150mg/day), taken for 12 weeks, in 164 patients (n=116 men and n=48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender, and then randomly assigned to naltrexone or placebo, and to either cognitive behavioral therapy, or a type of medical management. The two primary outcomes were cocaine and alcohol use. Significant gender by medication interactions were found for cocaine use via urine drug screens [3-way with time] and self-reports [2-way], for drug severity [2-way], and for alcohol use [2-way]. Type of psychosocial treatment did not affect outcomes. Thus, 150mg/day of naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use, and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women.

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Cocaine Metabolism in Humans after Use of Alcohol Clinical and Research Implications

Cited by 49 publications

References 59 publications

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

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

Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence

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