1. Academic Validation
  2. Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex

  • Drug Deliv. 2020 Dec;27(1):1501-1513. doi: 10.1080/10717544.2020.1837293.
Saurav Kumar Jha 1 Hee-Soo Han 2 Laxman Subedi 1 Rudra Pangeni 3 Jee Young Chung 4 Seho Kweon 5 Jeong Uk Choi 6 Youngro Byun 5 Yong-Hee Kim 2 4 Jin Woo Park 1 3
Affiliations

Affiliations

  • 1 Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Republic of Korea.
  • 2 Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, BK 21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, Republic of Korea.
  • 3 College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Republic of Korea.
  • 4 Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
  • 5 Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 6 College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
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 α-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 (Papp ), 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 Papp 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.

Keywords

Etoposide; bile acid transporter-mediated uptake; nanoemulsion; oral absorption; oral bioavailability; permeability.

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