Wang Q, Simpao A, Sun L, Falk J L, Lau C E
Department of Psychology, Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA.
Psychopharmacology (Berl). 2001 Jan;153(3):341-52. doi: 10.1007/s002130000568.
Oral cocaine is more effective than IV cocaine by pharmacokinetic and pharmacodynamic analysis. One explanation is involvement of the active metabolite, norcocaine, in cocaine's effects.
To evaluate norcocaine's contribution to oral cocaine's effects, norcocaine's effects as a parent compound were determined and compared to those of cocaine using a differential reinforcement of low rate (DRL 45-s) schedule and spontaneous activity (large and small movements) after IV and PO routes of administration.
The effects of cocaine and norcocaine on DRL performance (shorter-response and reinforcement rates) and spontaneous activity were investigated in 3-h sessions. The changes in effects across time (effect-time profiles) and dose-response curves (DRCs) were constructed to evaluate the duration of action and potency (ED50) of both drugs.
Under the DRL 45-s schedule, effect-time profiles showed both drugs via the two routes of administration significantly increasing and decreasing shorter-response rates and reinforcement rates, respectively. However, cocaine produced greater effects on shorterresponse rates than norcocaine, while both drugs produced comparable effects on reinforcement rates. For spontaneous activity, although IV cocaine, PO cocaine, and PO norcocaine dose- and time-dependently increased spontaneous activity, cocaine's effects were more profound than those of norcocaine. Effect-time profiles revealed that the duration of drug action was a function of dose, route, and behavioral paradigm used. According to ED50 values, IV cocaine was more effective than PO cocaine; however, PO cocaine was more effective than IV cocaine as judged by ED50 values corrected for absolute oral bioavailability.
Norcocaine's contribution to oral cocaine's effects on DRL performance is evident. Other mechanism(s), such as a greater acute tolerance to IV cocaine's effects than to PO cocaine's effects, can be excluded.
通过药代动力学和药效学分析，口服可卡因比静脉注射可卡因更有效。一种解释是活性代谢物去甲可卡因参与了可卡因的作用。
为了评估去甲可卡因对口服可卡因作用的贡献，确定了去甲可卡因作为母体化合物的作用，并将其与可卡因的作用进行比较，采用低速率差异强化（DRL 45秒）程序以及静脉注射和口服给药后的自发活动（大动作和小动作）。
在3小时的实验中研究了可卡因和去甲可卡因对DRL表现（较短反应和强化率）和自发活动的影响。构建了不同时间的效应变化（效应-时间曲线）和剂量-反应曲线（DRC），以评估两种药物的作用持续时间和效力（ED50）。
在DRL 45秒程序下，效应-时间曲线显示，两种给药途径的两种药物分别显著增加和降低了较短反应率和强化率。然而，可卡因对较短反应率的影响比去甲可卡因更大，而两种药物对强化率的影响相当。对于自发活动，虽然静脉注射可卡因、口服可卡因和口服去甲可卡因剂量和时间依赖性地增加了自发活动，但可卡因的作用比去甲可卡因更显著。效应-时间曲线表明，药物作用持续时间是所用剂量、给药途径和行为模式的函数。根据ED50值，静脉注射可卡因比口服可卡因更有效；然而，根据校正了绝对口服生物利用度的ED50值判断，口服可卡因比静脉注射可卡因更有效。
去甲可卡因对口服可卡因对DRL表现的作用贡献明显。可以排除其他机制，例如对静脉注射可卡因作用的急性耐受性大于对口服可卡因作用的急性耐受性。
