San Francisco Dept. of Veterans Affairs Medical Center and Department of Psychiatry, University of California, San Francisco, CA 94121, USA.
Exp Clin Psychopharmacol. 2011 Apr;19(2):95-104. doi: 10.1037/a0022950.
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.
乙醇改变了可卡因的肝生物转化，导致其转化为一种新型的活性代谢物——可乐因。由于首过代谢效应，口服给药可能会产生相对较高浓度的可乐因，而静脉或吸烟给药则不会。因此，我们比较了可卡因给药途径对可乐因形成和消除的影响。6 名有经验的可卡因使用者在大约 1 周的时间间隔内接受了 6 次测试。所有条件下均给予氘标记可卡因（d₅）。在口服乙醇 1.0 g/kg 或安慰剂后，分别给予口服可卡因-d₅ 2.0 mg/kg、静脉内可卡因-d₅ 1.0 mg/kg 和吸烟可卡因-d₅（200 mg）。所有条件下还给予了小剂量静脉内氘标记可乐因（d₃），以确定可乐因的形成。记录生理和主观效应，并通过气相色谱-质谱法测量血浆可卡因-d₅、可乐因-d₅、可乐因-d₃和苯甲酰古柯碱-d₅。约 24%（±11%）的静脉内可卡因转化为可乐因。口服途径（34%±20%）明显大于吸烟途径（18%±11%），且与静脉途径相比，可乐因的形成趋势更为显著。在每种途径中，与单独使用可卡因相比，可卡因和乙醇联合使用会导致心率和心率-血压乘积增加更大。吸烟或静脉内给药后，整体中毒效应随着时间的推移在同时给予可卡因和乙醇时显著增加。不同途径给予可卡因会通过肝脏首过效应改变形成的可乐因量。增加的心血管和主观效应可能解释了联合药物的毒性和流行。
