Lu K, Savaraj N, Feun L G, Guo Z G, Umsawasdi T, Loo T L
Division of Medicine, University of Texas M. D. Anderson Hospital and Tumor Institute, Houston.
Cancer Chemother Pharmacol. 1988;21(2):139-42. doi: 10.1007/BF00257360.
We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.
我们采用色谱和放射化学技术，研究了抗肿瘤生物碱高三尖杉酯碱（HHT）在麻醉犬体内的药代动力学和分布情况。将均匀标记有氚的HHT以每只动物200微居里的剂量静脉注射给5只犬，剂量为0.05至0.34毫克/千克。原形HHT以三相方式从血浆中消失，初始血浆半衰期为9.4±4.2分钟，中间半衰期为1.4±0.5小时，终末半衰期为40.6±4.6小时。血浆清除率为114.0±20.1毫升/千克-1小时-1，稳态分布容积为6.2±0.7升/千克。在72小时内，给药放射性的40.1%±4.0%经尿液排泄，其中17.8%±2.7%为原形HHT。HHT被广泛代谢为一种主要代谢物和两种次要代谢物。5小时内总放射性的胆汁排泄率为14.4%，其中2%为HHT。给药后4小时脑脊液中HHT浓度最高，约为同时期血浆浓度的40%。给药后5小时尸检时，HHT含量最高的是肝脏（7.4%），其次是小肠（2.5%）、胃（1.0%）、胰腺（0.8%）、肾脏（0.8%）和肺（0.7%）。心脏、脾脏、大肠和大脑中的含量均低于0.5%。然而，给药后24小时，肝脏中仍有4%的HHT，小肠中有1%，其他器官中不到1%。HHT在犬体内似乎被广泛代谢且部分留存于体内。
