Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | Drug Delivery |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/10717544.2020.1837293 |
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| author | Saurav Kumar Jha Hee-Soo Han Laxman Subedi Rudra Pangeni Jee Young Chung Seho Kweon Jeong Uk Choi Youngro Byun Yong-Hee Kim Jin Woo Park |
| author_facet | Saurav Kumar Jha Hee-Soo Han Laxman Subedi Rudra Pangeni Jee Young Chung Seho Kweon Jeong Uk Choi Youngro Byun Yong-Hee Kim Jin Woo Park |
| author_sort | Saurav Kumar Jha |
| collection | DOAJ |
| description | 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 Nα-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. |
| first_indexed | 2024-12-17T07:39:45Z |
| format | Article |
| id | doaj.art-6fc25124d83b44a3acf22ae82b59ce9d |
| institution | Directory Open Access Journal |
| issn | 1071-7544 1521-0464 |
| language | English |
| last_indexed | 2024-12-17T07:39:45Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Drug Delivery |
| spelling | doaj.art-6fc25124d83b44a3acf22ae82b59ce9d2022-12-21T21:58:11ZengTaylor & Francis GroupDrug Delivery1071-75441521-04642020-01-012711501151310.1080/10717544.2020.18372931837293Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complexSaurav Kumar Jha0Hee-Soo Han1Laxman Subedi2Rudra Pangeni3Jee Young Chung4Seho Kweon5Jeong Uk Choi6Youngro Byun7Yong-Hee Kim8Jin Woo Park9Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National UniversityDepartment of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, BK 21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National UniversityCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National UniversityDepartment of Bioengineering, Hanyang UniversityDepartment of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National UniversityCollege of Pharmacy, Chonnam National UniversityDepartment of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National UniversityDepartment of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, BK 21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National UniversityIn 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 Nα-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.http://dx.doi.org/10.1080/10717544.2020.1837293etoposidenanoemulsionpermeabilityoral bioavailabilitybile acid transporter-mediated uptakeoral absorption |
| spellingShingle | Saurav Kumar Jha Hee-Soo Han Laxman Subedi Rudra Pangeni Jee Young Chung Seho Kweon Jeong Uk Choi Youngro Byun Yong-Hee Kim Jin Woo Park Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex Drug Delivery etoposide nanoemulsion permeability oral bioavailability bile acid transporter-mediated uptake oral absorption |
| title | Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex |
| title_full | Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex |
| title_fullStr | Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex |
| title_full_unstemmed | Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex |
| title_short | Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex |
| title_sort | enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative lipid complex |
| topic | etoposide nanoemulsion permeability oral bioavailability bile acid transporter-mediated uptake oral absorption |
| url | http://dx.doi.org/10.1080/10717544.2020.1837293 |
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