Porter C J, Charman S A, Charman W N
Department of Pharmaceutics, Monash University, Parkville, Victoria, Australia.
J Pharm Sci. 1996 Apr;85(4):351-6. doi: 10.1021/js950221g.
Halofantrine hydrochloride is an important, highly lipophilic anti-malarial agent. A triple-cannulated anesthetized rat model was used to investigate the potential lymphatic transport of halofantrine (Hf). The effect of formulating Hf in vehicles representative of different physical (digestion) states of triglyceride lipid was also evaluated. The lipid vehicles were either a lipid solution, emulsion, or micellar system comprised of 50 microL of a 2:1 molar ratio of oleic acid:glycerol monooleate containing 2 mg of Hf free base. Lymph was collected from the mesenteric lymph duct, and blood was sampled from the jugular vein following intraduodenal infusion of the different formulations. Lymphatic transport was a major contributor to bioavailability as demonstrated by the recovery of up to approximately 20% of the administered dose in the intestinal lymph. The rank order effect of the vehicles for the promotion of lymphatic transport was micellar > emulsion > lipid solution. Lymphatic drug transport was predominantly associated with chylomicron-based transport. The extent of Hf absorption via the portal blood, estimated from the systemic plasma profiles in the lymph-cannulated rats, was largely independent of the administered formulations. These data indicate that lymphatic transport of the free base of Hf is a major contributor to oral bioavailability when formulated in appropriate lipid vehicles. The data suggest that formulation as increasingly disperse systems facilitates transport in this animal model.
盐酸卤泛群是一种重要的、高度亲脂性的抗疟药。采用三插管麻醉大鼠模型研究卤泛群（Hf）的潜在淋巴转运。还评估了将Hf制成代表甘油三酯脂质不同物理（消化）状态的载体的效果。脂质载体为脂质溶液、乳剂或胶束系统，由50微升含2毫克Hf游离碱的油酸与甘油单油酸酯摩尔比为2:1的混合物组成。在十二指肠内输注不同制剂后，从肠系膜淋巴管收集淋巴液，并从颈静脉采集血液样本。淋巴转运是生物利用度的主要贡献因素之一，在肠淋巴液中回收的给药剂量高达约20%即可证明。促进淋巴转运的载体的排序效应为胶束＞乳剂＞脂质溶液。淋巴药物转运主要与基于乳糜微粒的转运相关。根据淋巴管插管大鼠的全身血浆谱估计，Hf经门静脉血的吸收程度在很大程度上与给药制剂无关。这些数据表明，当制成适当的脂质载体时，Hf游离碱的淋巴转运是口服生物利用度的主要贡献因素。数据表明，在该动物模型中，制成越来越分散的系统有助于转运。
