Cocaethylene formation following ethanol and cocaine administration by different routes.

Abstract

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d₅) was administered in all conditions. Oral cocaine-d₅ 2.0 mg/kg, intravenous cocaine-d₅ 1.0 mg/kg, and smoked cocaine-d₅ (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d₃) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d₅, cocaethylene-d₅, cocaethylene-d₃, and benzoylecgonine-d₅ were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

“…The dose of ethanol used in the present study has been reported to elevate heart rate by 5.7 beats/min (Spaak et al, 2008). Similarly, combining ethanol with cocaine has been shown to significantly elevate heart rate in humans compared with cocaine alone (Herbst et al, 2011).…”

“…3). In an analogous fashion, ethanol has been reported to elevate cocaine exposure (Perez-Reyes, 1994;Farre et al, 1997) while serving as a transesterification substrate yielding CES1-mediated cocaethylene in humans (Herbst et al, 2011) and in other species (Roberts et al, 1993;Hedaya and Pan, 1996;Parker and Laizure, 2010). The significant elevation of heart rate upon combining ethanol with either dl-MPH or d-MPH (Fig.…”

“…This biotransformation product can serve as a biomarker for concomitant dl-MPH-ethanol exposure (Markowitz et al, 1999) analogous to the detection of the transesterification metabolite cocaethylene (ethylcocaine) evidencing cocaine-ethanol coabuse (Herbst et al, 2011). Over 80% of an oral dose of dl-MPH can be recovered in the urine (Redalieu et al, 1982) as the inactive (Patrick et al, 1981) hydrolysis metabolite ritalinic acid (Fig.…”

The effects of a humanized recombinant anti-cocaine monoclonal antibody on the disposition of cocaethylene in mice

“…When both ethanol and cocaine are present in the liver, the enzyme carboxylesterase-2 catalyzes a transesterification of the methyl ester moiety to an ethyl ester to produce the psychoactive metabolite cocaethylene [6]. In humans who ingest alcohol, between 18% and 34% of cocaine is metabolized to cocaethylene [7]. Like cocaine, cocaethylene has been shown to rapidly enter the brain where it blocks the dopamine transporter and prevents dopamine reuptake.…”

Kinetic characterization of human butyrylcholinesterase mutants for the hydrolysis of cocaethylene

“…With alcohol co-administration, ~24% (intravenous), ~34% (oral), or ~18% (smoked) of cocaine is converted to cocaethylene through transesterification. [18] Hence, a truly valuable mutant of human BChE for anti-cocaine enzyme therapy development should be efficient for not only cocaine, but also norcocaine and cocaethylene.…”