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A Non-Lipolysis Nanoemulsion Improved Oral Bioavailability by Reducing the First-Pass Metabolism of Raloxifene, and Related Absorption Mechanisms Being Studied.
- Source :
-
International journal of nanomedicine [Int J Nanomedicine] 2020 Aug 26; Vol. 15, pp. 6503-6518. Date of Electronic Publication: 2020 Aug 26 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- 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.<br />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.<br />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).<br />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.<br />Competing Interests: The authors report no conflicts of interest in this work.<br /> (© 2020 Ye et al.)
- Subjects :
- Administration, Oral
Animals
Biological Availability
Biological Transport
Cell Survival
Dogs
Emulsions administration & dosage
Female
Intestines physiology
Lymph metabolism
Madin Darby Canine Kidney Cells
Male
Polyethylene Glycols
Rats, Sprague-Dawley
Surface-Active Agents chemistry
Swine
Absorption, Physicochemical
Emulsions chemistry
Lipolysis
Nanoparticles chemistry
Raloxifene Hydrochloride metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1178-2013
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- International journal of nanomedicine
- Publication Type :
- Academic Journal
- Accession number :
- 32922013
- Full Text :
- https://doi.org/10.2147/IJN.S259993