Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs
Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs
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DOI：
10.1016/j.ejps.2004.12.006
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发表时间：
2005-03-01
影响因子：
4.6
通讯作者：
Hoffman, A
中科院分区：
文献类型：
--
作者：
Dahan, A;Hoffman, A
这项研究的目的是检查利用已知的乳清微粒流动阻断物质来研究药物在体内淋巴传输的可行性。给环己亚胺(3 mg/kg)、秋水仙碱(5 mg/kg)或十二指肠内注射Pluronic L-81(1 mg/h)所致乳糜管血流受阻的大鼠注射模型脂类分子维生素D-3(0.5 mg/kg)。比较这些实验模型与肠系膜淋巴管插管大鼠模型对维生素D3吸收的影响。采用口服D-木糖负荷试验验证其他肠道吸收功能未受影响。秋水仙碱治疗引起严重的不良反应，而Pluronic L-81和放线菌酮模型不影响其他吸收途径，也没有引起明显的不良反应。在这两种模型中维生素D3的吸收与肠系膜淋巴管插管模型(非淋巴相对生物利用度为25%)有很好的相关性，表明亲脂分子掺入乳糜管是淋巴吸收级联过程中的一个重要步骤。此外，数据表明，药物与乳胶粒的关联发生在其组装过程的早期阶段。结果还表明，淋巴吸收和门静脉血液吸收是不同的路径，不受彼此影响。总之，化学阻断乳胶粒流动为淋巴运输研究提供了一种潜在的途径，并可能阐明与脂类化合物吸收有关的过程。(C)2005 Elsevier B.V.保留所有权利。
The purpose of this study was to examine the feasibility of investigating the lymphatic transport of drugs in vivo utilizing known chylomicron flow blocking substances. Vitamin D-3 (0.5 mg/kg), a model lipophilic molecule, was administered to rats with blocked chylomicron flow, induced by either cycloheximide injection (3 mg/kg), colchicine injection (5 mg/kg) or intraduodenal infusion of pluronic L-81 (1 mg/h). The effect of these experimental models on the absorption of Vitamin D3 was compared to the outcomes of the mesenteric lymph duct cannulated rat model. The oral D-Xylose loading test was used to verify that other intestinal absorptive functions were not affected. Colchicine treatment induced severe adverse effects whereas pluronic L-81 and the cycloheximide models did not affect other absorption pathways and did not cause apparent adverse effects. Vitamin D3 absorption in these two models was in good correlation to the mesenteric lymph duct cannulation model (25% non-lymphatic relative bioavailability) indicating that the incorporation of the lipophilic molecule into the chylomicron is an essential step in the cascade of lymphatic absorption. Moreover, the data suggest that the drug association with the chylomicron occurs at an early stage of its assembly process. The results also specify that lymphatic absorption and portal blood absorption are separate pathways that are not affected by each other. In conclusion, the chemical blockage of chylomicron flow provides a potential approach for lymphatic transport investigation, and may elucidate processes involving in the absorption of lipophilic compounds. (c) 2005 Elsevier B.V. All rights reserved.