Porter C J, Charman S A, Humberstone A J, Charman W N
Department of Pharmaceutics, Monash University, Parkville, Victoria, Australia.
J Pharm Sci. 1996 Apr;85(4):357-61. doi: 10.1021/js9502229.
The intestinal lymphatic transport of halofantrine, an important, highly lipophilic antimalarial drug, has been studied in a conscious rat model after oral administration. In these studies, the lymphatic transport of Hf free base when coadministered with lipid was approximately 20% of the administered dose compared with 5% transport after administration of the HCl salt with or without lipid. These differences in transport can be attributed to the increased lipophilicity of the free base (relative to the HCl salt) thereby facilitating greater association of Hf base with the products of luminal lipid digestion and the subsequent interaction with the intestinally derived chylomicrons responsible for lymphatic drug transport. In contrast to previous results in an anesthetized rat model where lymphatic transport was dependent on the characteristics of the intraduodenally administered lipid formulations, the lymphatic transport of Hf base in the conscious rat was independent of both the class of administered lipid (triglyceride or fatty acid) and the extent of formulation dispersion (micellar lipid or lipid solution). Considering the different lymphatic transport profiles of Hf base in the anesthetized and conscious rat models, it is proposed that the lipid vehicle effects observed in the intraduodenally dosed anesthetized model most likely reflects the lack of gastric processing by preduodenal lipase and the shear action of the stomach otherwise present in the conscious rat model.
卤泛群是一种重要的、高度亲脂性的抗疟药物，口服给药后，在清醒大鼠模型中对其肠道淋巴转运进行了研究。在这些研究中，与脂质共同给药时，游离碱形式的卤泛群的淋巴转运量约为给药剂量的20%，而给予盐酸盐（无论是否与脂质一起给药）后的转运量为5%。转运上的这些差异可归因于游离碱（相对于盐酸盐）亲脂性的增加，从而促进了卤泛群碱与腔内脂质消化产物的更多结合，以及随后与负责淋巴药物转运的肠道来源乳糜微粒的相互作用。与先前在麻醉大鼠模型中的结果相反（在该模型中，淋巴转运取决于十二指肠内给药脂质制剂的特性），清醒大鼠中卤泛群碱的淋巴转运与给药脂质的类别（甘油三酯或脂肪酸）和制剂分散程度（胶束脂质或脂质溶液）均无关。考虑到卤泛群碱在麻醉和清醒大鼠模型中的不同淋巴转运情况，有人提出，在十二指肠内给药的麻醉模型中观察到的脂质载体效应很可能反映了十二指肠前脂肪酶缺乏胃内处理作用，以及清醒大鼠模型中原本存在的胃部剪切作用。
