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Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.
- Source :
-
Journal of Pharmaceutical Sciences . Feb2016, Vol. 105 Issue 2, p925-934. 10p. 1 Diagram, 1 Chart, 4 Graphs. - Publication Year :
- 2016
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Abstract
- The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carriermediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISPVal) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISPVal was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 timeseenhanced apparent permeability (Papp) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (Peff) in mice, 6.32 ? 3.12 and 5.20 ? 2.81 x 10-5 cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral antiinfluenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00223549
- Volume :
- 105
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 119921602
- Full Text :
- https://doi.org/10.1016/j.xphs.2015.11.036