Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Royal Parade, Parkville, Victoria, Australia 3052.
Mol Pharm. 2011 Aug 1;8(4):1132-9. doi: 10.1021/mp100462d. Epub 2011 Jun 1.
Elevated systemic levels of triglyceride-rich lipoproteins (TRL) are a risk factor for the development of atherosclerosis. In patients with metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma fatty acids and insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal lipid transport and lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of lipids and a model lipophilic drug (halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H lipids and drug. Changes to biliary lipid output and lymphatic lipid and drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic lipid and drug transport. The increased lipids in lymph were not derived from bile or the intestinal blood supply (fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced lipids was evident. Increasing plasma levels of TRL therefore stimulated lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of drug treatments.
富含甘油三酯的脂蛋白（TRL）的系统水平升高是动脉粥样硬化发展的一个风险因素。在代谢综合征（MetS）患者中，肠道 TRL 的过度产生导致了高系统 TRL 水平，最近的研究表明，MetS 中的系统性变化，如血浆脂肪酸和胰岛素抵抗的增加，刺激了肠道 TRL 的产生。本研究检查了系统 TRL 的增加是否会影响肠道脂质转运和脂蛋白组装途径，并评估这些变化对脂质和模型亲脂性药物（卤泛群）的吸收和淋巴转运的影响。肠系膜淋巴管或胆管插管大鼠静脉注射生理盐水或（14）C 标记的乳糜微粒（CM）（以增加系统 TRL）和十二指肠内（3）H 脂质和药物。随后检查了胆汁脂质输出和淋巴脂质和药物转运的变化。增加系统 TRL 浓度刺激了淋巴脂质和药物转运的显著增加。淋巴中的增加的脂质不是来自胆汁或肠道血液供应（脂肪酸或静脉内输注的（14）C-CM）。相反，十二指肠来源的脂质的淋巴转运增加。因此，TRL 水平升高会通过正反馈过程刺激脂质吸收和淋巴转运。数据还表明，由于系统 TRL 水平升高而导致的肠道 TRL 形成的变化可能会影响高度亲脂性药物的吸收，从而影响药物治疗的重现性。
