Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharm Sci
2016 Feb 01;1052:925-934. doi: 10.1016/j.xphs.2015.11.036.
Show Gene links
Show Anatomy links
Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.
Incecayir T
,
Sun J
,
Tsume Y
,
Xu H
,
Gose T
,
Nakanishi T
,
Tamai I
,
Hilfinger J
,
Lipka E
,
Amidon GL
.
???displayArticle.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 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 (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) 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.
Abed,
Treatment of respiratory virus infections.
2006, Pubmed
Abed,
Treatment of respiratory virus infections.
2006,
Pubmed
Balimane,
Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir.
1998,
Pubmed
,
Xenbase
Cass,
Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers.
1999,
Pubmed
Cattoli,
H5N1 Virus Evolution in Europe-An Updated Overview.
2009,
Pubmed
Chong,
In vitro permeability through caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system.
1996,
Pubmed
Collin,
Vaccine production capacity for seasonal and pandemic (H1N1) 2009 influenza.
2009,
Pubmed
Dawood,
Emergence of a novel swine-origin influenza A (H1N1) virus in humans.
2009,
Pubmed
Eriksson,
The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: in situ rat intestinal perfusion studies.
2010,
Pubmed
Fagerholm,
Comparison between permeability coefficients in rat and human jejunum.
1996,
Pubmed
Gupta,
Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers.
2009,
Pubmed
Gupta,
Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach.
2011,
Pubmed
Gupta,
Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.
2013,
Pubmed
Hayden,
Developing new antiviral agents for influenza treatment: what does the future hold?
2009,
Pubmed
He,
Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.
1999,
Pubmed
Ikematsu,
Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza.
2011,
Pubmed
Incecayir,
Comparison of the permeability of metoprolol and labetalol in rat, mouse, and Caco-2 cells: use as a reference standard for BCS classification.
2013,
Pubmed
Kim,
Identification of a human valacyclovirase: biphenyl hydrolase-like protein as valacyclovir hydrolase.
2003,
Pubmed
Lai,
Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase.
2008,
Pubmed
Li,
Epidemiology of human infections with avian influenza A(H7N9) virus in China.
2014,
Pubmed
Li,
Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071.
1998,
Pubmed
Liu,
Synthesis and anti-influenza activities of carboxyl alkoxyalkyl esters of 4-guanidino-Neu5Ac2en (zanamivir).
2007,
Pubmed
Liu,
Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir.
2011,
Pubmed
Miller,
Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.
2010,
Pubmed
Nakanishi,
Na+- and Cl--coupled active transport of carnitine by the amino acid transporter ATB(0,+) from mouse colon expressed in HRPE cells and Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Schade,
Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.
2015,
Pubmed
Shetty,
Peramivir for the treatment of influenza.
2012,
Pubmed
Sugawara,
Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2.
2000,
Pubmed
,
Xenbase
Sun,
Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.
2010,
Pubmed
Sun,
Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs.
2002,
Pubmed
