Pollock B G, Perel J M
Department of Psychiatry, University of Pittsburgh, School of Medicine, PA 15213.
Psychopharmacology (Berl). 1992;109(1-2):57-62. doi: 10.1007/BF02245480.
The hemodynamic, cardiographic, and initial pharmacokinetic characteristics of the de novo administration of the 2-hydroxymetabolite (2-OH-IMI) of imipramine (IMI), compared with its parent was studied in a swine preparation. Cardiac output, arterial pressure, and the continuous electrocardiogram were assessed after the intravenous administration of the drug or its metabolite. Plasma, sampled over 120 min and CSF sampled at 60 min were analyzed by reverse phase HPLC with spectroflurometric detection. Equilibrium dialyses were performed on plasma sampled at 60 min. 2-OH-IMI, in doses of 5-6 mg/kg, compared to dosages of IMI up to 8.5 mg/kg, produced a significantly greater incidence of life-threatening arrhythmias, and caused profound and significant decreases in blood pressure and cardiac output. 2-OH-IMI had a smaller volume of distribution (Vd) and shorter half-life. CNS penetration, as estimated by CSF/plasma ratios, was significantly greater for 2-OH-IMI. These phenomena were partly accounted for by significantly less protein binding for the hydroxymetabolite. It is concluded that 2-OH-IMI has increased penetrance into the CNS despite a smaller Vd and that it is significantly more cardiotoxic than its parent.
在猪实验模型中，研究了与丙咪嗪（IMI）母体相比，丙咪嗪2-羟基代谢物（2-OH-IMI）从头给药的血流动力学、心电图及初始药代动力学特征。静脉注射药物或其代谢物后，评估心输出量、动脉压和连续心电图。通过反相高效液相色谱荧光检测法分析给药后120分钟内采集的血浆样本以及给药60分钟时采集的脑脊液样本。对给药60分钟时采集的血浆样本进行平衡透析。与高达8.5mg/kg的IMI剂量相比，5-6mg/kg剂量的2-OH-IMI导致危及生命心律失常的发生率显著更高，并引起血压和心输出量显著且深度下降。2-OH-IMI的分布容积（Vd）较小，半衰期较短。通过脑脊液/血浆比率估算，2-OH-IMI的中枢神经系统穿透性显著更高。这些现象部分归因于羟基代谢物的蛋白结合显著减少。研究得出结论，尽管2-OH-IMI的Vd较小，但其对中枢神经系统的穿透性增加，并且其心脏毒性显著高于其母体。
