Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica

Autores
Mottier, Maria de Lourdes; Virkel, Guillermo Leon; Solana, Hugo Daniel; Alvarez, Luis Ignacio; Sallés Abal, Juan Manuel; Lanusse, Carlos Edmundo
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Triclabendazole (TCBZ) is an halogenated trematodicidal benzimidazole compound extensively used in veterinary medicine. It is active against immature and adult stages of the liver fluke Fasciola hepatica. Free and conjugated TCBZ metabolites have been identified in the bile of treated sheep. The experimental aims were to characterize the in vitro patterns of TCBZ biotransformation both in the animal host (sheep liver microsomes) and target parasite (F. hepatica microsomal preparation); and to compare the ex vivo diffusion of TCBZ parent drug and its oxidized metabolites (TCBZ sulphoxide [TCBZSO], TCBZ sulphone [TCBZSO2], and TCBZ-hydroxy derivatives) into F. hepatica. Additionally, the octanol-water partition coefficients for TCBZ and all its metabolites were estimated as an indicator of the relationship between drug lipophilicity and diffusion into the target parasite. Drug/metabolites concentrations were quantified by HPLC after sample clean up and a solvent-mediated chemical extraction. Sheep liver microsomes metabolized TCBZ into its sulphoxide and sulphone metabolites after 30min of incubation. The rate of TCBZ sulphoxidation in the liver was significantly greater (p<0.01) than that observed for the sulphonation of TCBZSO. The trematode parasite oxidized TCBZ into its sulphoxide metabolite after 60min of incubation at a metabolic rate of 0.09 nmol min-1 mg protein-1. TCBZ and all its oxidized metabolic products were recovered from F. hepatica as early as 15 min after their ex vivo incubation in a Kreb's Ringer Tris buffer. However, the diffusion of the hydroxy-derivatives into the fluke was lower than that observed for TCBZ, TCBZSO and TCBZSO2. There was a high correlation (r = 0.82) between drug lipophilicity (expressed as octanol-water partition coefficients) and drug availability measured within the parasite. Unlike the uptake pattern previously observed for albendazole, the parent TCBZ and its sulphoxide and sulphone metabolites showed a similar ability to penetrate into the trematode parasite. Understanding the relationship between TCBZ metabolism, the relative pharmacological potency of its metabolic products and their ability to reach the target parasite may be critical to optimize its flukicidal activity, particularly when TCBZ resistant flukes have been already isolated in the field.
Fil: Mottier, Maria de Lourdes. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Virkel, Guillermo Leon. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Solana, Hugo Daniel. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
Fil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
Fil: Sallés Abal, Juan Manuel. Dirección General de Laboratorios Veterinarios Miguel Rubino; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
Materia
triclabendazole
biotransformation
parasite uptake
Fasciola hepatica
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:11336/111643
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepaticaMottier, Maria de LourdesVirkel, Guillermo LeonSolana, Hugo DanielAlvarez, Luis IgnacioSallés Abal, Juan ManuelLanusse, Carlos Edmundotriclabendazolebiotransformationparasite uptakeFasciola hepaticahttps://purl.org/becyt/ford/4.3https://purl.org/becyt/ford/4Triclabendazole (TCBZ) is an halogenated trematodicidal benzimidazole compound extensively used in veterinary medicine. It is active against immature and adult stages of the liver fluke Fasciola hepatica. Free and conjugated TCBZ metabolites have been identified in the bile of treated sheep. The experimental aims were to characterize the in vitro patterns of TCBZ biotransformation both in the animal host (sheep liver microsomes) and target parasite (F. hepatica microsomal preparation); and to compare the ex vivo diffusion of TCBZ parent drug and its oxidized metabolites (TCBZ sulphoxide [TCBZSO], TCBZ sulphone [TCBZSO2], and TCBZ-hydroxy derivatives) into F. hepatica. Additionally, the octanol-water partition coefficients for TCBZ and all its metabolites were estimated as an indicator of the relationship between drug lipophilicity and diffusion into the target parasite. Drug/metabolites concentrations were quantified by HPLC after sample clean up and a solvent-mediated chemical extraction. Sheep liver microsomes metabolized TCBZ into its sulphoxide and sulphone metabolites after 30min of incubation. The rate of TCBZ sulphoxidation in the liver was significantly greater (p<0.01) than that observed for the sulphonation of TCBZSO. The trematode parasite oxidized TCBZ into its sulphoxide metabolite after 60min of incubation at a metabolic rate of 0.09 nmol min-1 mg protein-1. TCBZ and all its oxidized metabolic products were recovered from F. hepatica as early as 15 min after their ex vivo incubation in a Kreb's Ringer Tris buffer. However, the diffusion of the hydroxy-derivatives into the fluke was lower than that observed for TCBZ, TCBZSO and TCBZSO2. There was a high correlation (r = 0.82) between drug lipophilicity (expressed as octanol-water partition coefficients) and drug availability measured within the parasite. Unlike the uptake pattern previously observed for albendazole, the parent TCBZ and its sulphoxide and sulphone metabolites showed a similar ability to penetrate into the trematode parasite. Understanding the relationship between TCBZ metabolism, the relative pharmacological potency of its metabolic products and their ability to reach the target parasite may be critical to optimize its flukicidal activity, particularly when TCBZ resistant flukes have been already isolated in the field.Fil: Mottier, Maria de Lourdes. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Virkel, Guillermo Leon. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Solana, Hugo Daniel. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Sallés Abal, Juan Manuel. Dirección General de Laboratorios Veterinarios Miguel Rubino; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaTaylor & Francis Ltd2008-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/111643Mottier, Maria de Lourdes; Virkel, Guillermo Leon; Solana, Hugo Daniel; Alvarez, Luis Ignacio; Sallés Abal, Juan Manuel; et al.; Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica; Taylor & Francis Ltd; Xenobiotica; 34; 11-12; 9-2008; 1043-10570049-8254CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/abs/10.1080/00498250400015285info:eu-repo/semantics/altIdentifier/doi/10.1080/00498250400015285info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:50Zoai:ri.conicet.gov.ar:11336/111643instacron: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 09:59:50.643CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
title Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
spellingShingle Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
Mottier, Maria de Lourdes
triclabendazole
biotransformation
parasite uptake
Fasciola hepatica
title_short Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
title_full Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
title_fullStr Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
title_full_unstemmed Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
title_sort Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica
dc.creator.none.fl_str_mv Mottier, Maria de Lourdes
Virkel, Guillermo Leon
Solana, Hugo Daniel
Alvarez, Luis Ignacio
Sallés Abal, Juan Manuel
Lanusse, Carlos Edmundo
author Mottier, Maria de Lourdes
author_facet Mottier, Maria de Lourdes
Virkel, Guillermo Leon
Solana, Hugo Daniel
Alvarez, Luis Ignacio
Sallés Abal, Juan Manuel
Lanusse, Carlos Edmundo
author_role author
author2 Virkel, Guillermo Leon
Solana, Hugo Daniel
Alvarez, Luis Ignacio
Sallés Abal, Juan Manuel
Lanusse, Carlos Edmundo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv triclabendazole
biotransformation
parasite uptake
Fasciola hepatica
topic triclabendazole
biotransformation
parasite uptake
Fasciola hepatica
purl_subject.fl_str_mv https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
dc.description.none.fl_txt_mv Triclabendazole (TCBZ) is an halogenated trematodicidal benzimidazole compound extensively used in veterinary medicine. It is active against immature and adult stages of the liver fluke Fasciola hepatica. Free and conjugated TCBZ metabolites have been identified in the bile of treated sheep. The experimental aims were to characterize the in vitro patterns of TCBZ biotransformation both in the animal host (sheep liver microsomes) and target parasite (F. hepatica microsomal preparation); and to compare the ex vivo diffusion of TCBZ parent drug and its oxidized metabolites (TCBZ sulphoxide [TCBZSO], TCBZ sulphone [TCBZSO2], and TCBZ-hydroxy derivatives) into F. hepatica. Additionally, the octanol-water partition coefficients for TCBZ and all its metabolites were estimated as an indicator of the relationship between drug lipophilicity and diffusion into the target parasite. Drug/metabolites concentrations were quantified by HPLC after sample clean up and a solvent-mediated chemical extraction. Sheep liver microsomes metabolized TCBZ into its sulphoxide and sulphone metabolites after 30min of incubation. The rate of TCBZ sulphoxidation in the liver was significantly greater (p<0.01) than that observed for the sulphonation of TCBZSO. The trematode parasite oxidized TCBZ into its sulphoxide metabolite after 60min of incubation at a metabolic rate of 0.09 nmol min-1 mg protein-1. TCBZ and all its oxidized metabolic products were recovered from F. hepatica as early as 15 min after their ex vivo incubation in a Kreb's Ringer Tris buffer. However, the diffusion of the hydroxy-derivatives into the fluke was lower than that observed for TCBZ, TCBZSO and TCBZSO2. There was a high correlation (r = 0.82) between drug lipophilicity (expressed as octanol-water partition coefficients) and drug availability measured within the parasite. Unlike the uptake pattern previously observed for albendazole, the parent TCBZ and its sulphoxide and sulphone metabolites showed a similar ability to penetrate into the trematode parasite. Understanding the relationship between TCBZ metabolism, the relative pharmacological potency of its metabolic products and their ability to reach the target parasite may be critical to optimize its flukicidal activity, particularly when TCBZ resistant flukes have been already isolated in the field.
Fil: Mottier, Maria de Lourdes. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Virkel, Guillermo Leon. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Solana, Hugo Daniel. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
Fil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
Fil: Sallés Abal, Juan Manuel. Dirección General de Laboratorios Veterinarios Miguel Rubino; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina
description Triclabendazole (TCBZ) is an halogenated trematodicidal benzimidazole compound extensively used in veterinary medicine. It is active against immature and adult stages of the liver fluke Fasciola hepatica. Free and conjugated TCBZ metabolites have been identified in the bile of treated sheep. The experimental aims were to characterize the in vitro patterns of TCBZ biotransformation both in the animal host (sheep liver microsomes) and target parasite (F. hepatica microsomal preparation); and to compare the ex vivo diffusion of TCBZ parent drug and its oxidized metabolites (TCBZ sulphoxide [TCBZSO], TCBZ sulphone [TCBZSO2], and TCBZ-hydroxy derivatives) into F. hepatica. Additionally, the octanol-water partition coefficients for TCBZ and all its metabolites were estimated as an indicator of the relationship between drug lipophilicity and diffusion into the target parasite. Drug/metabolites concentrations were quantified by HPLC after sample clean up and a solvent-mediated chemical extraction. Sheep liver microsomes metabolized TCBZ into its sulphoxide and sulphone metabolites after 30min of incubation. The rate of TCBZ sulphoxidation in the liver was significantly greater (p<0.01) than that observed for the sulphonation of TCBZSO. The trematode parasite oxidized TCBZ into its sulphoxide metabolite after 60min of incubation at a metabolic rate of 0.09 nmol min-1 mg protein-1. TCBZ and all its oxidized metabolic products were recovered from F. hepatica as early as 15 min after their ex vivo incubation in a Kreb's Ringer Tris buffer. However, the diffusion of the hydroxy-derivatives into the fluke was lower than that observed for TCBZ, TCBZSO and TCBZSO2. There was a high correlation (r = 0.82) between drug lipophilicity (expressed as octanol-water partition coefficients) and drug availability measured within the parasite. Unlike the uptake pattern previously observed for albendazole, the parent TCBZ and its sulphoxide and sulphone metabolites showed a similar ability to penetrate into the trematode parasite. Understanding the relationship between TCBZ metabolism, the relative pharmacological potency of its metabolic products and their ability to reach the target parasite may be critical to optimize its flukicidal activity, particularly when TCBZ resistant flukes have been already isolated in the field.
publishDate 2008
dc.date.none.fl_str_mv 2008-09
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/11336/111643
Mottier, Maria de Lourdes; Virkel, Guillermo Leon; Solana, Hugo Daniel; Alvarez, Luis Ignacio; Sallés Abal, Juan Manuel; et al.; Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica; Taylor & Francis Ltd; Xenobiotica; 34; 11-12; 9-2008; 1043-1057
0049-8254
CONICET Digital
CONICET
url http://hdl.handle.net/11336/111643
identifier_str_mv Mottier, Maria de Lourdes; Virkel, Guillermo Leon; Solana, Hugo Daniel; Alvarez, Luis Ignacio; Sallés Abal, Juan Manuel; et al.; Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica; Taylor & Francis Ltd; Xenobiotica; 34; 11-12; 9-2008; 1043-1057
0049-8254
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1080/00498250400015285
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publisher.none.fl_str_mv Taylor & Francis Ltd
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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