title: 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.
authors.affiliation: San Francisco Dept. of Veterans Affairs Medical Center and Department of Psychiatry, University of California, San Francisco, CA 94121, USA. ellen.herbst@va.gov
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Herbst
authors.forename: Debra S
authors.initials: DS
authors.lastname: Harris
authors.forename: E Thomas
authors.initials: ET
authors.lastname: Everhart
authors.forename: John
authors.initials: J
authors.lastname: Mendelson
authors.forename: Peyton
authors.initials: P
authors.lastname: Jacob
authors.forename: Reese T
authors.initials: RT
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001519:Behavior / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D010919:Placebos; D012907:Smoking
chemical_list: D010919:Placebos; D000431:Ethanol; C066444:cocaethylene; D003042:Cocaine