tetano
Editor, Senior Moderator
J Pharm Sci. 2016 Feb;105(2):925-34. doi: 10.1016/j.xphs.2015.11.036.
[h=1]Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.[/h] Incecayir T[SUP]1[/SUP], Sun J[SUP]2[/SUP], Tsume Y[SUP]2[/SUP], Xu H[SUP]2[/SUP], Gose T[SUP]3[/SUP], Nakanishi T[SUP]3[/SUP], Tamai I[SUP]3[/SUP], Hilfinger J[SUP]4[/SUP], Lipka E[SUP]4[/SUP], Amidon GL[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) 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-ISP-Val 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 times-enhanced 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 ? 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 anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells.
Copyright ? 2016 American Pharmacists Association?. Published by Elsevier Inc. All rights reserved.
[h=4]KEYWORDS:[/h] Caco-2 cells; absorption potential; active transport; cell culture; membrane transport and transporters; peptide transporters; permeability; prodrugs
PMID: 26869437 [PubMed - in process]
[h=1]Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.[/h] Incecayir T[SUP]1[/SUP], Sun J[SUP]2[/SUP], Tsume Y[SUP]2[/SUP], Xu H[SUP]2[/SUP], Gose T[SUP]3[/SUP], Nakanishi T[SUP]3[/SUP], Tamai I[SUP]3[/SUP], Hilfinger J[SUP]4[/SUP], Lipka E[SUP]4[/SUP], Amidon GL[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) 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-ISP-Val 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 times-enhanced 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 ? 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 anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells.
Copyright ? 2016 American Pharmacists Association?. Published by Elsevier Inc. All rights reserved.
[h=4]KEYWORDS:[/h] Caco-2 cells; absorption potential; active transport; cell culture; membrane transport and transporters; peptide transporters; permeability; prodrugs
PMID: 26869437 [PubMed - in process]