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Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.
- Source :
-
Drug delivery [Drug Deliv] 2020 Dec; Vol. 27 (1), pp. 1501-1513. - Publication Year :
- 2020
-
Abstract
- In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic N <superscript>α</superscript> -deoxycholyl-l-lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability ( P <subscript>app</subscript> ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the P <subscript>app</subscript> by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.
- Subjects :
- A549 Cells
Administration, Oral
Animals
Biological Availability
Caco-2 Cells
Cell Line, Tumor
Citric Acid chemistry
Deoxycholic Acid metabolism
Emulsions metabolism
Glycerol chemistry
HT29 Cells
Humans
Intestinal Absorption drug effects
Permeability drug effects
Polyethylene Glycols chemistry
Rats
Rats, Sprague-Dawley
Deoxycholic Acid chemistry
Emulsions chemistry
Etoposide chemistry
Lipids chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0464
- Volume :
- 27
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Drug delivery
- Publication Type :
- Academic Journal
- Accession number :
- 33107339
- Full Text :
- https://doi.org/10.1080/10717544.2020.1837293