Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses

Autores
Gualdesi, María Soledad; Briñon, Margarita Cristina; Quevedo, Mario Alfredo
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Lamivudine (3TC) is an antiviral drug used to treat Acquired Immunodeficiency Syndrome (AIDS) in humans with a vastly demonstrated clinical efficacy. However the rapid emergence of resistant viral strains limits its efficacy, thus several strategies, such as the design of prodrugs, have been widely applied to optimize its pharmacotherapeutic properties. In this work we deal with the study of the intestinal permeation of 3TC and two novel prodrugs of 3TC, namely 3TC-Etha and 3TC-Buta, by using rat intestinal segments and applying the gut sac in vitro technique. An adequate bioanalytical method (sample preparation and quantitative analysis) was fully developed and validated for the quantitation of these three compounds. A low permeability coefficient (Papp 0.408 ± 0.049 x10-4 cm/min) was found for 3TC, with no statistically significant difference in its apical-to-basal and. basal-to-apical permeability. We concluded that 3TC permeates through the intestinal tissue by passive diffusion, with no intervention of efflux mechanism on the apical side of the enterocyte. Regarding the prodrugs, both 3TC-Etha and 3TC-Buta were able to increase 3TC permeability (2 and 10 times, respectively). However none of these compounds were able to cross the intestinal tissue in their intact form. In the case of 3TC-Etha, the permeability of the intact compound is impaired by a P-glycoprotein (P-gp) mediated efflux, evidenced by the high permeability coefficient (2.170 ± 0.122 x10-4 cm/min) determined in the presence of verapamil on the apical side of the enterocyte. On the other hand, 3TC-Buta was not subjected to efflux mechanisms on the apical side of the enterocyte, but is efficiently subjected to enzymatic hydrolysis during the permeation process. In light of these results, molecular modeling (docking and molecular dynamics) procedures were applied to further study the structural features that confers this different behavior of these two compound respect to P-gp mediated efflux, stressing the potential of combining experimental and theoretical studies for the design of 3TC prodrugs with high oral bioavailabilities.
Fil: Gualdesi, María Soledad. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Briñon, Margarita Cristina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
Materia
INTESTINAL ABSORPTION
LAMIVUDINE
MOLECULAR MODELING
P-GLYCOPROTEIN
PRODRUGS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/197815

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network_name_str CONICET Digital (CONICET)
spelling Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analysesGualdesi, María SoledadBriñon, Margarita CristinaQuevedo, Mario AlfredoINTESTINAL ABSORPTIONLAMIVUDINEMOLECULAR MODELINGP-GLYCOPROTEINPRODRUGShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Lamivudine (3TC) is an antiviral drug used to treat Acquired Immunodeficiency Syndrome (AIDS) in humans with a vastly demonstrated clinical efficacy. However the rapid emergence of resistant viral strains limits its efficacy, thus several strategies, such as the design of prodrugs, have been widely applied to optimize its pharmacotherapeutic properties. In this work we deal with the study of the intestinal permeation of 3TC and two novel prodrugs of 3TC, namely 3TC-Etha and 3TC-Buta, by using rat intestinal segments and applying the gut sac in vitro technique. An adequate bioanalytical method (sample preparation and quantitative analysis) was fully developed and validated for the quantitation of these three compounds. A low permeability coefficient (Papp 0.408 ± 0.049 x10-4 cm/min) was found for 3TC, with no statistically significant difference in its apical-to-basal and. basal-to-apical permeability. We concluded that 3TC permeates through the intestinal tissue by passive diffusion, with no intervention of efflux mechanism on the apical side of the enterocyte. Regarding the prodrugs, both 3TC-Etha and 3TC-Buta were able to increase 3TC permeability (2 and 10 times, respectively). However none of these compounds were able to cross the intestinal tissue in their intact form. In the case of 3TC-Etha, the permeability of the intact compound is impaired by a P-glycoprotein (P-gp) mediated efflux, evidenced by the high permeability coefficient (2.170 ± 0.122 x10-4 cm/min) determined in the presence of verapamil on the apical side of the enterocyte. On the other hand, 3TC-Buta was not subjected to efflux mechanisms on the apical side of the enterocyte, but is efficiently subjected to enzymatic hydrolysis during the permeation process. In light of these results, molecular modeling (docking and molecular dynamics) procedures were applied to further study the structural features that confers this different behavior of these two compound respect to P-gp mediated efflux, stressing the potential of combining experimental and theoretical studies for the design of 3TC prodrugs with high oral bioavailabilities.Fil: Gualdesi, María Soledad. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Briñon, Margarita Cristina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaElsevier Science2012-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/197815Gualdesi, María Soledad; Briñon, Margarita Cristina; Quevedo, Mario Alfredo; Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses; Elsevier Science; European Journal of Pharmaceutical Sciences; 47; 5; 12-2012; 965-9780928-0987CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0928098712003843info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejps.2012.10.002info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:47Zoai:ri.conicet.gov.ar:11336/197815instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:43:48.116CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
title Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
spellingShingle Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
Gualdesi, María Soledad
INTESTINAL ABSORPTION
LAMIVUDINE
MOLECULAR MODELING
P-GLYCOPROTEIN
PRODRUGS
title_short Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
title_full Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
title_fullStr Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
title_full_unstemmed Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
title_sort Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses
dc.creator.none.fl_str_mv Gualdesi, María Soledad
Briñon, Margarita Cristina
Quevedo, Mario Alfredo
author Gualdesi, María Soledad
author_facet Gualdesi, María Soledad
Briñon, Margarita Cristina
Quevedo, Mario Alfredo
author_role author
author2 Briñon, Margarita Cristina
Quevedo, Mario Alfredo
author2_role author
author
dc.subject.none.fl_str_mv INTESTINAL ABSORPTION
LAMIVUDINE
MOLECULAR MODELING
P-GLYCOPROTEIN
PRODRUGS
topic INTESTINAL ABSORPTION
LAMIVUDINE
MOLECULAR MODELING
P-GLYCOPROTEIN
PRODRUGS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Lamivudine (3TC) is an antiviral drug used to treat Acquired Immunodeficiency Syndrome (AIDS) in humans with a vastly demonstrated clinical efficacy. However the rapid emergence of resistant viral strains limits its efficacy, thus several strategies, such as the design of prodrugs, have been widely applied to optimize its pharmacotherapeutic properties. In this work we deal with the study of the intestinal permeation of 3TC and two novel prodrugs of 3TC, namely 3TC-Etha and 3TC-Buta, by using rat intestinal segments and applying the gut sac in vitro technique. An adequate bioanalytical method (sample preparation and quantitative analysis) was fully developed and validated for the quantitation of these three compounds. A low permeability coefficient (Papp 0.408 ± 0.049 x10-4 cm/min) was found for 3TC, with no statistically significant difference in its apical-to-basal and. basal-to-apical permeability. We concluded that 3TC permeates through the intestinal tissue by passive diffusion, with no intervention of efflux mechanism on the apical side of the enterocyte. Regarding the prodrugs, both 3TC-Etha and 3TC-Buta were able to increase 3TC permeability (2 and 10 times, respectively). However none of these compounds were able to cross the intestinal tissue in their intact form. In the case of 3TC-Etha, the permeability of the intact compound is impaired by a P-glycoprotein (P-gp) mediated efflux, evidenced by the high permeability coefficient (2.170 ± 0.122 x10-4 cm/min) determined in the presence of verapamil on the apical side of the enterocyte. On the other hand, 3TC-Buta was not subjected to efflux mechanisms on the apical side of the enterocyte, but is efficiently subjected to enzymatic hydrolysis during the permeation process. In light of these results, molecular modeling (docking and molecular dynamics) procedures were applied to further study the structural features that confers this different behavior of these two compound respect to P-gp mediated efflux, stressing the potential of combining experimental and theoretical studies for the design of 3TC prodrugs with high oral bioavailabilities.
Fil: Gualdesi, María Soledad. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Briñon, Margarita Cristina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
description Lamivudine (3TC) is an antiviral drug used to treat Acquired Immunodeficiency Syndrome (AIDS) in humans with a vastly demonstrated clinical efficacy. However the rapid emergence of resistant viral strains limits its efficacy, thus several strategies, such as the design of prodrugs, have been widely applied to optimize its pharmacotherapeutic properties. In this work we deal with the study of the intestinal permeation of 3TC and two novel prodrugs of 3TC, namely 3TC-Etha and 3TC-Buta, by using rat intestinal segments and applying the gut sac in vitro technique. An adequate bioanalytical method (sample preparation and quantitative analysis) was fully developed and validated for the quantitation of these three compounds. A low permeability coefficient (Papp 0.408 ± 0.049 x10-4 cm/min) was found for 3TC, with no statistically significant difference in its apical-to-basal and. basal-to-apical permeability. We concluded that 3TC permeates through the intestinal tissue by passive diffusion, with no intervention of efflux mechanism on the apical side of the enterocyte. Regarding the prodrugs, both 3TC-Etha and 3TC-Buta were able to increase 3TC permeability (2 and 10 times, respectively). However none of these compounds were able to cross the intestinal tissue in their intact form. In the case of 3TC-Etha, the permeability of the intact compound is impaired by a P-glycoprotein (P-gp) mediated efflux, evidenced by the high permeability coefficient (2.170 ± 0.122 x10-4 cm/min) determined in the presence of verapamil on the apical side of the enterocyte. On the other hand, 3TC-Buta was not subjected to efflux mechanisms on the apical side of the enterocyte, but is efficiently subjected to enzymatic hydrolysis during the permeation process. In light of these results, molecular modeling (docking and molecular dynamics) procedures were applied to further study the structural features that confers this different behavior of these two compound respect to P-gp mediated efflux, stressing the potential of combining experimental and theoretical studies for the design of 3TC prodrugs with high oral bioavailabilities.
publishDate 2012
dc.date.none.fl_str_mv 2012-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/197815
Gualdesi, María Soledad; Briñon, Margarita Cristina; Quevedo, Mario Alfredo; Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses; Elsevier Science; European Journal of Pharmaceutical Sciences; 47; 5; 12-2012; 965-978
0928-0987
CONICET Digital
CONICET
url http://hdl.handle.net/11336/197815
identifier_str_mv Gualdesi, María Soledad; Briñon, Margarita Cristina; Quevedo, Mario Alfredo; Intestinal permeability of lamivudine (3TC) and two novel 3TC prodrugs. Experimental and theoretical analyses; Elsevier Science; European Journal of Pharmaceutical Sciences; 47; 5; 12-2012; 965-978
0928-0987
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejps.2012.10.002
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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application/pdf
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dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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