Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2T9, Canada; Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
J Pharmacol Toxicol Methods. 2024 Sep-Oct;129:107548. doi: 10.1016/j.vascn.2024.107548. Epub 2024 Aug 2.
Scientists have developed and employed various models to investigate intestinal lymphatic uptake. One approach involves using specific blocking agents to influence the chylomicron-mediated lymphatic absorption of drugs. Currently utilized models include pluronic L-81, puromycin, vinca alkaloids, colchicine, and cycloheximide. This review offers a thorough analysis of the diverse models utilized, evaluating existing reports while delineating the gaps in current research. It also explores pharmacokinetic related aspects of intestinal lymphatic uptake pathway and its blockage through the discussed models. Pluronic L-81 has a reversible effect, minimal toxicity, and unique mode of action. Yet, it lacks clinical reports on chylomicron pathway blockage, likely due to low concentrations used. Puromycin and vinca alkaloids, though documented for toxicity, lack information on their application in drug intestinal lymphatic uptake. Other vinca alkaloids show promise in affecting triglyceride profiles and represent possible agents to test as blockers. Colchicine and cycloheximide, widely used in pharmaceutical development, have demonstrated efficacy, with cycloheximide preferred for lower toxicity. However, further investigation into effective and toxic doses of colchicine in humans is needed to understand its clinical impact. The review additionally followed the complete journey of oral lymphatic targeting drugs from intake to excretion, provided a pharmacokinetic equation considering the intestinal lymphatic pathway for assessing bioavailability. Moreover, the possible application of urinary data as a non-invasive way to measure the uptake of drugs through intestinal lymphatics was illustrated, and the likelihood of drug interactions when specific blockers are employed in human subjects was underscored.
科学家们已经开发并采用了各种模型来研究肠道淋巴管摄取。一种方法是使用特定的阻断剂来影响药物的乳糜微粒介导的淋巴管吸收。目前使用的模型包括 Pluronic L-81、嘌呤霉素、长春花生物碱、秋水仙碱和环己亚胺。本综述对所使用的各种模型进行了全面分析，评估了现有报告，同时阐明了当前研究中的空白。它还探讨了通过所讨论的模型对肠道淋巴管摄取途径及其阻断的药代动力学相关方面。Pluronic L-81 具有可逆作用、低毒性和独特的作用模式。然而，由于使用的浓度低，它缺乏关于乳糜微粒途径阻断的临床报告。嘌呤霉素和长春花生物碱虽然有关于毒性的记录，但缺乏关于它们在药物肠道淋巴管摄取中的应用的信息。其他长春花生物碱在影响甘油三酯谱方面显示出潜力，可能是作为阻断剂进行测试的候选药物。秋水仙碱和环己亚胺广泛用于药物开发，已被证明有效，环己亚胺因其毒性较低而更受青睐。然而，需要进一步研究秋水仙碱在人体内的有效和毒性剂量，以了解其临床影响。该综述还详细描述了口服淋巴靶向药物从摄入到排泄的完整过程，提供了考虑肠道淋巴途径的药代动力学方程，用于评估生物利用度。此外，还说明了将特定阻断剂用于人体时药物相互作用的可能性，并说明了利用尿数据作为衡量肠道淋巴管摄取药物的非侵入性方法的可能性。
