Pollock B G, Everett G, Perel J M
Department of Psychiatry, University of Pittsburgh, School of Medicine, Pennsylvania.
Neuropsychopharmacology. 1992 Jan;6(1):1-10.
The potential cardiotoxicity of the hydroxymetabolites of nortriptyline (NT) has been raised by inferential data from clinical studies and by the experimentally demonstrated cardiac effects of 2-OH-imipramine. Cardiac output, arterial pressure, and a continuous electrocardiogram were assessed after intravenous de novo administration of NT or its hydroxymetabolites to 41 swine. NT at doses ranging from 3.5 to 7 mg base per kilogram caused significantly more arrhythmias than did E-10-hydroxynortriptyline (E-10-OH-NT) but was not significantly different from Z-10-hydroxynortriptyline (Z-10-OH-NT) in this effect. Z-10-OH-NT, in contrast, to its geometrical isomer caused marked bradycardia, and decrements in blood pressure and cardiac output. NT and Z-10-OH-NT, but not E-10-OH-NT, produced dose-correlated declines in cardiac output. The hydroxymetabolites had smaller volumes of distribution, shorter half-lives and larger free fractions compared with NT. The differing cardiotoxicity of the hydroxymetabolites could not be accounted for by differing pharmacokinetic properties.
临床研究的推断数据以及实验证明的2-羟基丙咪嗪的心脏效应引发了对去甲替林（NT）羟基代谢物潜在心脏毒性的关注。对41头猪静脉内首次给予NT或其羟基代谢物后，评估心输出量、动脉压和连续心电图。每千克3.5至7毫克碱基剂量的NT引起的心律失常明显多于E-10-羟基去甲替林（E-10-OH-NT），但在这一效应上与Z-10-羟基去甲替林（Z-10-OH-NT）无显著差异。相比之下，Z-10-OH-NT与其几何异构体不同，可引起明显的心动过缓以及血压和心输出量下降。NT和Z-10-OH-NT（而非E-10-OH-NT）可导致心输出量呈剂量相关性下降。与NT相比，羟基代谢物的分布容积更小、半衰期更短且游离分数更大。羟基代谢物不同的心脏毒性无法用不同的药代动力学特性来解释。
