Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University (Parkville Campus), 399 Royal Parade, Parkville, Victoria 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Int J Pharm. 2021 Mar 1;596:120247. doi: 10.1016/j.ijpharm.2021.120247. Epub 2021 Jan 22.
Orlistat is a pancreatic lipase (PL) inhibitor that inhibits dietary lipid absorption and is used to treat obesity. The oral bioavailability of orlistat is considered zero after administration in standard formulations. This is advantageous in the treatment of obesity. However, if orlistat absorption could be improved it has the potential to treat diseases such as acute and critical illnesses where PL transport to the systemic circulation via gut lymph promotes organ failure. Orlistat is highly lipophilic and may associate with intestinal lipid absorption pathways into lymph. Here we investigate the potential to improve orlistat lymph and systemic uptake through intestinal administration in lipid formulations (LFs). The effect of lipid type, lipid dose, orlistat dose, and infusion time on lymph and systemic availability of orlistat was investigated. After administration in all LFs, orlistat concentrations in lymph were greater than in plasma, suggesting direct transport via lymph. Lymph and plasma orlistat derivative concentrations were ~8-fold greater after administration in a long-chain fatty acid (LC-FA) compared to a lipid-free, LC triglyceride (LC-TG) or medium-chain FA (MC-FA) formulation. Overall, administration of orlistat in a LC-FA formulation promotes lymph and systemic uptake which may enable treatment of diseases associated with elevated systemic PL activity.
奥利司他是一种胰脂肪酶（PL）抑制剂，可抑制膳食脂质吸收，用于治疗肥胖症。标准制剂给药后，奥利司他的口服生物利用度被认为为零。这在肥胖症治疗中是有利的。然而，如果可以改善奥利司他的吸收，它有可能治疗急性和危重病等疾病，在这些疾病中，PL 通过肠道淋巴输送到全身循环会促进器官衰竭。奥利司他具有很强的亲脂性，可能与肠道脂质吸收途径一起进入淋巴。在这里，我们研究了通过肠道给予脂质制剂（LFs）来改善奥利司他淋巴和全身摄取的潜力。研究了脂质类型、脂质剂量、奥利司他剂量和输注时间对奥利司他淋巴和全身利用率的影响。在所有 LFs 给药后，淋巴中奥利司他的浓度高于血浆，表明通过淋巴直接转运。与无脂质、长链甘油三酯（LC-TG）或中链脂肪酸（MC-FA）制剂相比，长链脂肪酸（LC-FA）给药后，淋巴和血浆中奥利司他衍生物的浓度增加了约 8 倍。总体而言，LC-FA 制剂中奥利司他的给药促进了淋巴和全身摄取，这可能使治疗与全身 PL 活性升高相关的疾病成为可能。
