The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs

Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were de...

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Autores: Tsume, Yasuhiro, Borrás Bermejo, Blanca, Amidon, Gordon L.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/57908
Acceso en línea:https://doi.org/10.3390/ph7020169
http://hdl.handle.net/10459.1/57908
Access Level:acceso abierto
Palabra clave:Gemcitabine prodrug
Floxuridine prodrug
Mouse in situ perfusion
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spelling The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogsTsume, YasuhiroBorrás Bermejo, BlancaAmidon, Gordon L.Gemcitabine prodrugFloxuridine prodrugMouse in situ perfusionDipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.This work was supported by grants NIGMD-2R01GM037188.MDPI2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.3390/ph7020169http://hdl.handle.net/10459.1/57908reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a https://doi.org/10.3390/ph7020169Pharmaceuticals, 2014, vol. 7, p. 169-191cc-by (c) Tsume et al., 2016info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/oai:recercat.cat:10459.1/579082026-05-29T05:05:01Z
dc.title.none.fl_str_mv The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
title The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
spellingShingle The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
Tsume, Yasuhiro
Gemcitabine prodrug
Floxuridine prodrug
Mouse in situ perfusion
title_short The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
title_full The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
title_fullStr The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
title_full_unstemmed The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
title_sort The dipeptide monoester prodrugs of floxuridine and gemcitabine - feasibility of orally administrable nucleoside analogs
dc.creator.none.fl_str_mv Tsume, Yasuhiro
Borrás Bermejo, Blanca
Amidon, Gordon L.
author Tsume, Yasuhiro
author_facet Tsume, Yasuhiro
Borrás Bermejo, Blanca
Amidon, Gordon L.
author_role author
author2 Borrás Bermejo, Blanca
Amidon, Gordon L.
author2_role author
author
dc.subject.none.fl_str_mv Gemcitabine prodrug
Floxuridine prodrug
Mouse in situ perfusion
topic Gemcitabine prodrug
Floxuridine prodrug
Mouse in situ perfusion
description Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.
publishDate 2014
dc.date.none.fl_str_mv 2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.3390/ph7020169
http://hdl.handle.net/10459.1/57908
url https://doi.org/10.3390/ph7020169
http://hdl.handle.net/10459.1/57908
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.3390/ph7020169
Pharmaceuticals, 2014, vol. 7, p. 169-191
dc.rights.none.fl_str_mv cc-by (c) Tsume et al., 2016
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
rights_invalid_str_mv cc-by (c) Tsume et al., 2016
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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