ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

Detalhes bibliográficos
Autor(a) principal: Noël, F.
Data de Publicação: 2016
Outros Autores: Nascimento-Viana, J. B., Romeiro, Luiz Antonio Soares, Silva, Renata Oliveira, Lemes, L. F. N., Oliveira, Andressa Souza de, Giorno, T. B. S., Fernandes, P. D., Silva, C. L. M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UnB
Texto Completo: http://repositorio.unb.br/handle/10482/30084
http://dx.doi.org/10.1590/1414-431x20165542
Resumo: This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.
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spelling ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasiaHiperplasiaSegurançaPermeabilidadeThis study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.Associação Brasileira de Divulgação Científica2017-12-07T05:17:20Z2017-12-07T05:17:20Z2016info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfNOËL, F. et al. ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia. Brazilian Journal of Medical and Biological Research, Ribeirão Preto, v. 49, n. 12, e5542, 2016. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200603&lng=en&nrm=iso>. Acesso em: 12 mar. 2018. Epub Nov 24, 2016. doi: http://dx.doi.org/10.1590/1414-431x20165542.http://repositorio.unb.br/handle/10482/30084http://dx.doi.org/10.1590/1414-431x20165542Brazilian Journal of Medical and Biological Research - This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0). Fonte: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200603&lng=en&nrm=iso. Acesso em: 12 mar. 2018.info:eu-repo/semantics/openAccessNoël, F.Nascimento-Viana, J. B.Romeiro, Luiz Antonio SoaresSilva, Renata OliveiraLemes, L. F. N.Oliveira, Andressa Souza deGiorno, T. B. S.Fernandes, P. D.Silva, C. L. M.engreponame:Repositório Institucional da UnBinstname:Universidade de Brasília (UnB)instacron:UNB2023-05-24T00:10:14Zoai:repositorio.unb.br:10482/30084Repositório InstitucionalPUBhttps://repositorio.unb.br/oai/requestrepositorio@unb.bropendoar:2023-05-24T00:10:14Repositório Institucional da UnB - Universidade de Brasília (UnB)false
dc.title.none.fl_str_mv ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
title ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
spellingShingle ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
Noël, F.
Hiperplasia
Segurança
Permeabilidade
title_short ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
title_full ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
title_fullStr ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
title_full_unstemmed ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
title_sort ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia
author Noël, F.
author_facet Noël, F.
Nascimento-Viana, J. B.
Romeiro, Luiz Antonio Soares
Silva, Renata Oliveira
Lemes, L. F. N.
Oliveira, Andressa Souza de
Giorno, T. B. S.
Fernandes, P. D.
Silva, C. L. M.
author_role author
author2 Nascimento-Viana, J. B.
Romeiro, Luiz Antonio Soares
Silva, Renata Oliveira
Lemes, L. F. N.
Oliveira, Andressa Souza de
Giorno, T. B. S.
Fernandes, P. D.
Silva, C. L. M.
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Noël, F.
Nascimento-Viana, J. B.
Romeiro, Luiz Antonio Soares
Silva, Renata Oliveira
Lemes, L. F. N.
Oliveira, Andressa Souza de
Giorno, T. B. S.
Fernandes, P. D.
Silva, C. L. M.
dc.subject.por.fl_str_mv Hiperplasia
Segurança
Permeabilidade
topic Hiperplasia
Segurança
Permeabilidade
description This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.
publishDate 2016
dc.date.none.fl_str_mv 2016
2017-12-07T05:17:20Z
2017-12-07T05:17:20Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv NOËL, F. et al. ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia. Brazilian Journal of Medical and Biological Research, Ribeirão Preto, v. 49, n. 12, e5542, 2016. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200603&lng=en&nrm=iso>. Acesso em: 12 mar. 2018. Epub Nov 24, 2016. doi: http://dx.doi.org/10.1590/1414-431x20165542.
http://repositorio.unb.br/handle/10482/30084
http://dx.doi.org/10.1590/1414-431x20165542
identifier_str_mv NOËL, F. et al. ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia. Brazilian Journal of Medical and Biological Research, Ribeirão Preto, v. 49, n. 12, e5542, 2016. Disponível em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2016001200603&lng=en&nrm=iso>. Acesso em: 12 mar. 2018. Epub Nov 24, 2016. doi: http://dx.doi.org/10.1590/1414-431x20165542.
url http://repositorio.unb.br/handle/10482/30084
http://dx.doi.org/10.1590/1414-431x20165542
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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dc.publisher.none.fl_str_mv Associação Brasileira de Divulgação Científica
publisher.none.fl_str_mv Associação Brasileira de Divulgação Científica
dc.source.none.fl_str_mv reponame:Repositório Institucional da UnB
instname:Universidade de Brasília (UnB)
instacron:UNB
instname_str Universidade de Brasília (UnB)
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institution UNB
reponame_str Repositório Institucional da UnB
collection Repositório Institucional da UnB
repository.name.fl_str_mv Repositório Institucional da UnB - Universidade de Brasília (UnB)
repository.mail.fl_str_mv repositorio@unb.br
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