Objective: A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies.
Methods: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model.
Results: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had two-fold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05).
Conclusion: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.

Keywords: non-lipolysis nanoemulsion, raloxifene, first-pass metabolism, stability, bioavailability, endocytosis


中文翻译：

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一种非脂解纳米乳液通过减少雷洛昔芬的首过代谢来提高口服生物利用度，并且正在研究相关的吸收机制。

目的：通过体外和体内研究，设计了一种非脂解纳米乳剂（NNE），通过肠道UDP-葡萄糖醛酸基转移酶（UGTs）减少雷洛昔芬（RAL）的首过代谢，以增加RAL的口服吸收。
方法：通过脂解和UGT代谢系统评价NNE的体外稳定性。在大鼠和猪中研究了 NNE 的口服生物利用度。最后，通过大鼠原位单次肠道灌注（SPIP）、Madin-Darby犬肾（MDCK）细胞模型和淋巴阻断模型研究了NNE的吸收机制。
结果：pre-NNE由棕榈酸异丙酯、亚油酸、Cremophor RH40和乙醇组成，重量比为3.33:1.67:3:2。与RAL的脂解纳米乳（RAL-LNE）相比，RAL-NNE在体外胃肠缓冲液、脂解和UGT代谢系统中更稳定（p < 0.05）。在大鼠中，NNE（203.30%）和LNE（205.89%）相对于混悬剂组的口服生物利用度显着提高。然而，与悬浮液相比，口服 NNE 后，猪的相对生物利用度为 541.28%，生物利用度是 LNE 的两倍（p< 0.05)。RAL-NNE主要在空肠吸收，在大鼠肠道具有高渗透性。SPIP 和 MDCK 细胞模型的结果表明，RAL-NNE 通过由小窝蛋白和网格蛋白介导的内吞作用被吸收。与 LNE 相比，NNE 显着改善了另一种吸收途径，即淋巴转运（环己酰亚胺作为阻断剂）（p < 0.05）。
结论：成功开发了一种NNE，可降低RAL在肠道内的首过代谢，增强其淋巴转运，从而提高口服生物利用度。总而言之，NNE 是一种很有前途的口服药物载体，具有显着的首过代谢。

关键词：非脂解纳米乳, 雷洛昔芬, 首过代谢, 稳定性, 生物利用度, 内吞作用