A Non-Lipolysis Nanoemulsion Improved Oral Bioavailability by Reducing the First-Pass Metabolism of Raloxifene, and Related Absorption Mechanisms Being Studied

Abstract

Jing-Yi Ye,1 Zhong-Yun Chen,1 Chuan-Li Huang,1 Bei Huang,2 Yu-Rong Zheng,2 Ying-Feng Zhang,1 Ban-Yi Lu,2 Lin He,2 Chang-Shun Liu3 ,* Xiao-Ying Long1,4, * 1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 2School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 3School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chang-Shun LiuSouthern Medical University, No. 1023-1063 of Shatai South Road, Guangzhou, Guangdong 510515, People’s Republic of ChinaTel [phone]Email [email protected] LongGuangdong Pharmaceutical University, No. 280 of Waihuan East Road, Guangzhou, Guangdong 510006, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: 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

Keywords

• non-lipolysis nanoemulsion
• raloxifene
• first-pass metabolism
• stability
• bioavailability
• endocytosis