Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complexopen access
- Authors
- Jha, Saurav Kumar; Han, Hee-Soo; Subedi, Laxman; Pangeni, Rudra; Chung, Jee Young; Kweon, Seho; Choi, Jeong Uk; Byun, Youngro; Kim, Yong-Hee; Park, Jin Woo
- Issue Date
- Jan-2020
- Publisher
- TAYLOR & FRANCIS LTD
- Keywords
- Etoposide; nanoemulsion; permeability; oral bioavailability; bile acid transporter-mediated uptake; oral absorption
- Citation
- DRUG DELIVERY, v.27, no.1, pp.1501 - 1513
- Indexed
- SCIE
SCOPUS
- Journal Title
- DRUG DELIVERY
- Volume
- 27
- Number
- 1
- Start Page
- 1501
- End Page
- 1513
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/5176
- DOI
- 10.1080/10717544.2020.1837293
- ISSN
- 1071-7544
- 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 (alpha)-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-app ), 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-app 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.
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