Sgaragli G P, Valoti M, Palmi M, Frosini M, Giovannini M G, Bianchi L, Della Corte L
Centro Interdipartimentale di Ricerca sul Metabolismo dei Farmaci Neuropsicotropi, Istituto di Scienze Farmacologiche, Facolt' di Farmacia, Universit' degli Studi di Siena, Italy.
J Pharm Pharmacol. 1995 Sep;47(9):782-90. doi: 10.1111/j.2042-7158.1995.tb06741.x.
A single oral dose of 90 mg kg-1 chlorimipramine or chlorpromazine, corresponding to 54.5 or 55.9 mumol, respectively, was given to male Sprague-Dawley rats and concentrations of parent drugs and their N-desmethyl metabolites measured by gas chromatography in plasma and major organs (brain, liver, lung, kidney, heart, spleen and peritoneal fat). In the case of chlorimipramine, N-desmethyl metabolite levels were consistently higher than those of the parent drug for the entire observation period of 24 h in all tissues except fat, while lower N-desmethyl metabolite/parent compound ratios were observed for chlorpromazine. N-Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination-rate limited, while those of chlorpromazine were formation-rate limited. In all analysed organs, the maximu detectable drug+metabolite concentrations accounted for only 2.3 and 4.6% of the initial dose of chlorimipramine and chlorpromazine. Chlorpromazine treatment gave rise to an area under the total amount-time curve (AUC0-24) for parent drug+metabolites, 3.9-fold that for chlorimipraine. Closer scrutiny discloses a conversion ratio of parent compound to N-desmethyl metabolite of 1.1 for chlorpromazine and of 2.2 for chlorimipramine, indicating the greater efficiency of chlorimipramine metabolism in all compartments. The expected high conversion index found in the liver (2.3) reaches its maximum of 5.4 in the lung. Fractional data analysis of chlorimipramine and chlorpromazine distribution patterns revealed greater organ transfer for the N-desmethyl metabolites than for the more stably-located parent compounds. The N-desmethyl metabolites of chlorimipramine apparently moved from liver to lung, kidney and spleen, whereas N-desmethylchlopromazine moved preferentially to the brain and lung tissue. This single dose study of chlorimipramine and chlorpromazine kinetics, highlights the two distinct dispositional processes at work in the rat in all likelihood, attributable to different absorption patterns, to a slower metabolism and, thus, to the longer persistence of chlorpromazine.
给雄性斯普拉格-道利大鼠口服单剂量90毫克/千克氯米帕明或氯丙嗪，分别相当于54.5或55.9微摩尔，通过气相色谱法测定血浆和主要器官（脑、肝、肺、肾、心、脾和腹膜脂肪）中母体药物及其N-去甲基代谢物的浓度。就氯米帕明而言，在除脂肪外的所有组织中，在24小时的整个观察期内，N-去甲基代谢物水平始终高于母体药物，而氯丙嗪的N-去甲基代谢物/母体化合物比率较低。氯米帕明的N-去甲基代谢物动力学似乎受消除速率限制，而氯丙嗪的则受生成速率限制。在所有分析的器官中，最大可检测到的药物+代谢物浓度仅占氯米帕明和氯丙嗪初始剂量的2.3%和4.6%。氯丙嗪治疗使母体药物+代谢物的总量-时间曲线下面积（AUC0-24）是氯米帕明的3.9倍。仔细观察发现，氯丙嗪母体化合物向N-去甲基代谢物的转化率为1.1，氯米帕明为2.2，表明氯米帕明在所有区室中的代谢效率更高。在肝脏中发现的预期高转化指数（2.3）在肺中达到最大值5.4。氯米帕明和氯丙嗪分布模式的分数数据分析表明，N-去甲基代谢物比定位更稳定的母体化合物具有更大的器官转移。氯米帕明的N-去甲基代谢物显然从肝脏转移到肺、肾和脾，而N-去甲基氯丙嗪则优先转移到脑和肺组织。这项关于氯米帕明和氯丙嗪动力学的单剂量研究突出了大鼠体内可能存在的两种不同处置过程，这可能归因于不同的吸收模式、较慢的代谢以及氯丙嗪更长的存留时间。
