Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
Eur J Pharm Biopharm. 2022 Jul;176:122-132. doi: 10.1016/j.ejpb.2022.05.015. Epub 2022 May 25.
Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.
口服给予化疗药物，如多西紫杉醇（DTX），有望显著降低副作用并增加给药频率。然而，它们往往口服生物利用度较差，限制了其口服应用。膳食脂质，如甘油三酯，有利于淋巴转运而不是静脉系统，绕过首过代谢。受此启发，我们开发了一种 DTX 的甘油三酯样前药（命名为 OATG），并探索了脂质类型对 OATG 口服递送的影响。在大鼠中的血浆谱表明，基于长链甘油三酯（LCT）的脂质配方（LBLF）比中链甘油三酯（MCT）更适合 OATG 的递送。与口服 Taxotere 或 DTX LBLF 相比，OATG LBLF 引起明显增强的吸收，分别导致相对生物利用度提高 6.11 倍或 2.47 倍。脂质赋形剂和 TG 样前药的协同肠道行为促进了前药的口服吸收。在比格犬中也检查了前药制剂的有效性，绝对生物利用度高达 41.08%，与对照 DTX 组（8%）形成鲜明对比。此外，OATG 口服制剂可以进行密集给药计划，无过敏、胃肠道和血液毒性。当前的策略为化疗提供了一种有效的脂质配方和有希望的机会。
