Tella S R, Goldberg S R
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC.
Psychopharmacology (Berl). 1993;112(4):497-502. doi: 10.1007/BF02244900.
The time course of change in plasma levels of cocaine and its major metabolite benzoylecgonine following 3 mg/kg IV cocaine and the pharmacokinetic interaction between cocaine and several monoamine uptake inhibitors were investigated in conscious rats implanted with arterial and venous cannulae. The IV bolus administration of 3 mg/kg cocaine resulted in plasma levels of 1276 +/- 53 ng/ml cocaine at 0.5 min following its injection and the levels then rapidly declined to 768 +/- 110 ng/ml by 2 min. Thereafter, the decline of plasma cocaine levels was relatively slow. Plasma benzoylecgonine levels were similar at 0.5 and 2 min following cocaine injection but increased gradually over the next 25 min. Pretreatment with the norepinephrine-selective uptake inhibitors desipramine and nisoxetine, the serotonin-selective uptake inhibitor fluoxetine or the dopamine-selective uptake inhibitor GBR 12909 all enhanced plasma levels of cocaine after a 3 mg/kg IV bolus injection at 0.5, but not at 5 min after injection. The enhancement of plasma cocaine levels by GBR 12909 was of greater magnitude than that produced by desipramine, nisoxetine or fluoxetine. These agents, with the exception of the high dose (10 mg/kg) of GBR 12909, did not significantly alter plasma levels of benzoylecgonine measured at either 0.5 or 5 min following cocaine injection. These results indicate that monoamine uptake inhibitors can alter or interfere with the pharmacokinetics of cocaine and that this interaction is not due to a change in the biotransformation of cocaine. It is suggested that the central monoamine uptake sites serving as rapid distribution sites for cocaine may play a role in this pharmacokinetic interaction.
在植入动脉和静脉插管的清醒大鼠中，研究了静脉注射3mg/kg可卡因后，血浆中可卡因及其主要代谢产物苯甲酰爱康宁水平的变化时间过程，以及可卡因与几种单胺摄取抑制剂之间的药代动力学相互作用。静脉推注3mg/kg可卡因后，注射后0.5分钟血浆可卡因水平为1276±53ng/ml，然后迅速下降，到2分钟时降至768±110ng/ml。此后，血浆可卡因水平下降相对缓慢。可卡因注射后0.5分钟和2分钟时血浆苯甲酰爱康宁水平相似，但在接下来的25分钟内逐渐升高。用去甲肾上腺素选择性摄取抑制剂地昔帕明和尼索西汀、血清素选择性摄取抑制剂氟西汀或多巴胺选择性摄取抑制剂GBR 12909预处理，在静脉推注3mg/kg后0.5分钟而非注射后5分钟，均提高了血浆可卡因水平。GBR 12909对血浆可卡因水平的提高幅度大于地昔帕明、尼索西汀或氟西汀。除高剂量（10mg/kg）GBR 12909外，这些药物在可卡因注射后0.5分钟或5分钟时均未显著改变所测血浆苯甲酰爱康宁水平。这些结果表明，单胺摄取抑制剂可改变或干扰可卡因的药代动力学，且这种相互作用并非由于可卡因生物转化的改变所致。提示作为可卡因快速分布位点的中枢单胺摄取位点可能在这种药代动力学相互作用中起作用。
