Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.2174/18723128112069990013 http://hdl.handle.net/11449/227425 |
Resumo: | The prodrug hydroximethylnitrofurazone (NFOH) presents antichagasic activity with greatly reduced toxicity compared to its drug matrix nitrofurazone (NF). Besides these new characteristics, the prodrug was more active against the parasite T. cruzi amastigotes. These advantages make the prodrug a possible therapeutic alternative for the treatment of both acute and the chronic phase of Chagas disease. However, the knowledge of pharmacokinetic profile is crucial to evaluate the feasibility of a new drug. In this study, our objective was to evaluate the in vivo formation of NF from the NFOH single administration and to evaluate its pharmacokinetic profile and compared it to NF administration. A bioanalytical method to determine the NF and NFOH by LCMS/MS was developed and validated to perform these investigations. Male albino rabbits (n=15) received NF intravenously and orally in doses of 6.35 and 63.5 mg / kg respectively, and NFOH, 80.5 mg / kg orally. The serial blood samples were processed and analyzed by mass spectrometry. The system operated in positive and negative modes for the analites determination, under elution of the mobile phase 50:50 water: methanol. The administration of NFOH allowed the calculation of pharmacokinetic parameters for the prodrug, and the NF obtained from NFOH administration. Using the pharmacokinetic profile obtained from the NF i.v. administration, the oral bioavailability of NF from the administered prodrug was obtained (60.1%) and, as a key parameter in a prodrug administration, should be considered in future studies. The i.v. and oral administrations of NF differ in the constant of elimination (0.04 vs 0.002) and elimination half-life (17.32 min vs 276.09 min) due to the low solubility of the drug that hinders the formation of molecular dispersions in the digestory tract. Still, there was observed no statistical differences were observed between the pharmacokinetic parameters of orally administered NF and NF obtained from NFOH. The calculated area under the curve (AUC 0-∞) showed that the exposure to the parental drug was fairly the same (844.79 vs 566.44) for NF and NF obtained from the prodrug administration. The tendency to higher NF's mean residence time (MRT) as observed in the prodrug administration (956.1 min vs 496.3 min) guarantees longer time for the action of the drug and it allows the expansion of the administration intervals. These findings, added with the beneficial characteristics of the prodrug encourage new efficacy tests towards the clinical use of NFOH. ©2013 Bentham Science Publishers. |
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Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbitsChagas diseaseHydroxymthylnitrofurazoneNitrofurazonePharmacokineticsMarco Antonio Ferraz Nogueira Filhoa, Elias Carvalho Padilhaa, Michel Leandro de Camposa,The prodrug hydroximethylnitrofurazone (NFOH) presents antichagasic activity with greatly reduced toxicity compared to its drug matrix nitrofurazone (NF). Besides these new characteristics, the prodrug was more active against the parasite T. cruzi amastigotes. These advantages make the prodrug a possible therapeutic alternative for the treatment of both acute and the chronic phase of Chagas disease. However, the knowledge of pharmacokinetic profile is crucial to evaluate the feasibility of a new drug. In this study, our objective was to evaluate the in vivo formation of NF from the NFOH single administration and to evaluate its pharmacokinetic profile and compared it to NF administration. A bioanalytical method to determine the NF and NFOH by LCMS/MS was developed and validated to perform these investigations. Male albino rabbits (n=15) received NF intravenously and orally in doses of 6.35 and 63.5 mg / kg respectively, and NFOH, 80.5 mg / kg orally. The serial blood samples were processed and analyzed by mass spectrometry. The system operated in positive and negative modes for the analites determination, under elution of the mobile phase 50:50 water: methanol. The administration of NFOH allowed the calculation of pharmacokinetic parameters for the prodrug, and the NF obtained from NFOH administration. Using the pharmacokinetic profile obtained from the NF i.v. administration, the oral bioavailability of NF from the administered prodrug was obtained (60.1%) and, as a key parameter in a prodrug administration, should be considered in future studies. The i.v. and oral administrations of NF differ in the constant of elimination (0.04 vs 0.002) and elimination half-life (17.32 min vs 276.09 min) due to the low solubility of the drug that hinders the formation of molecular dispersions in the digestory tract. Still, there was observed no statistical differences were observed between the pharmacokinetic parameters of orally administered NF and NF obtained from NFOH. The calculated area under the curve (AUC 0-∞) showed that the exposure to the parental drug was fairly the same (844.79 vs 566.44) for NF and NF obtained from the prodrug administration. The tendency to higher NF's mean residence time (MRT) as observed in the prodrug administration (956.1 min vs 496.3 min) guarantees longer time for the action of the drug and it allows the expansion of the administration intervals. These findings, added with the beneficial characteristics of the prodrug encourage new efficacy tests towards the clinical use of NFOH. ©2013 Bentham Science Publishers.Departamento de Princípios Ativos Naturais e Toxicologia UNESP, Rodovia Araraquara Jaú Km. 01, 14801-902 Araraquara, SPDepartamento de Princípios Ativos Naturais e Toxicologia UNESP, Rodovia Araraquara Jaú Km. 01, 14801-902 Araraquara, SPUniversidade Estadual Paulista (UNESP)Filho, Marco Antonio Ferraz Nogueira [UNESP]Padilha, Elias Carvalho [UNESP]de Campos, Michel Leandro [UNESP]de Pontes Machado, Diego Vinicius [UNESP]Davanço, Marcelo Gomes [UNESP]Pestana, Kelly Christina [UNESP]Chin, Chung Man [UNESP]Peccinini, Rosângela Gonçalves [UNESP]2022-04-29T07:13:15Z2022-04-29T07:13:15Z2013-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article58-64http://dx.doi.org/10.2174/18723128112069990013Drug Metabolism Letters, v. 7, n. 1, p. 58-64, 2013.1872-3128http://hdl.handle.net/11449/22742510.2174/187231281120699900132-s2.0-84891879595Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengDrug Metabolism Lettersinfo:eu-repo/semantics/openAccess2024-06-24T14:51:23Zoai:repositorio.unesp.br:11449/227425Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:05:38.689877Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
title |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
spellingShingle |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits Filho, Marco Antonio Ferraz Nogueira [UNESP] Chagas disease Hydroxymthylnitrofurazone Nitrofurazone PharmacokineticsMarco Antonio Ferraz Nogueira Filhoa, Elias Carvalho Padilhaa, Michel Leandro de Camposa, |
title_short |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
title_full |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
title_fullStr |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
title_full_unstemmed |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
title_sort |
Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits |
author |
Filho, Marco Antonio Ferraz Nogueira [UNESP] |
author_facet |
Filho, Marco Antonio Ferraz Nogueira [UNESP] Padilha, Elias Carvalho [UNESP] de Campos, Michel Leandro [UNESP] de Pontes Machado, Diego Vinicius [UNESP] Davanço, Marcelo Gomes [UNESP] Pestana, Kelly Christina [UNESP] Chin, Chung Man [UNESP] Peccinini, Rosângela Gonçalves [UNESP] |
author_role |
author |
author2 |
Padilha, Elias Carvalho [UNESP] de Campos, Michel Leandro [UNESP] de Pontes Machado, Diego Vinicius [UNESP] Davanço, Marcelo Gomes [UNESP] Pestana, Kelly Christina [UNESP] Chin, Chung Man [UNESP] Peccinini, Rosângela Gonçalves [UNESP] |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) |
dc.contributor.author.fl_str_mv |
Filho, Marco Antonio Ferraz Nogueira [UNESP] Padilha, Elias Carvalho [UNESP] de Campos, Michel Leandro [UNESP] de Pontes Machado, Diego Vinicius [UNESP] Davanço, Marcelo Gomes [UNESP] Pestana, Kelly Christina [UNESP] Chin, Chung Man [UNESP] Peccinini, Rosângela Gonçalves [UNESP] |
dc.subject.por.fl_str_mv |
Chagas disease Hydroxymthylnitrofurazone Nitrofurazone PharmacokineticsMarco Antonio Ferraz Nogueira Filhoa, Elias Carvalho Padilhaa, Michel Leandro de Camposa, |
topic |
Chagas disease Hydroxymthylnitrofurazone Nitrofurazone PharmacokineticsMarco Antonio Ferraz Nogueira Filhoa, Elias Carvalho Padilhaa, Michel Leandro de Camposa, |
description |
The prodrug hydroximethylnitrofurazone (NFOH) presents antichagasic activity with greatly reduced toxicity compared to its drug matrix nitrofurazone (NF). Besides these new characteristics, the prodrug was more active against the parasite T. cruzi amastigotes. These advantages make the prodrug a possible therapeutic alternative for the treatment of both acute and the chronic phase of Chagas disease. However, the knowledge of pharmacokinetic profile is crucial to evaluate the feasibility of a new drug. In this study, our objective was to evaluate the in vivo formation of NF from the NFOH single administration and to evaluate its pharmacokinetic profile and compared it to NF administration. A bioanalytical method to determine the NF and NFOH by LCMS/MS was developed and validated to perform these investigations. Male albino rabbits (n=15) received NF intravenously and orally in doses of 6.35 and 63.5 mg / kg respectively, and NFOH, 80.5 mg / kg orally. The serial blood samples were processed and analyzed by mass spectrometry. The system operated in positive and negative modes for the analites determination, under elution of the mobile phase 50:50 water: methanol. The administration of NFOH allowed the calculation of pharmacokinetic parameters for the prodrug, and the NF obtained from NFOH administration. Using the pharmacokinetic profile obtained from the NF i.v. administration, the oral bioavailability of NF from the administered prodrug was obtained (60.1%) and, as a key parameter in a prodrug administration, should be considered in future studies. The i.v. and oral administrations of NF differ in the constant of elimination (0.04 vs 0.002) and elimination half-life (17.32 min vs 276.09 min) due to the low solubility of the drug that hinders the formation of molecular dispersions in the digestory tract. Still, there was observed no statistical differences were observed between the pharmacokinetic parameters of orally administered NF and NF obtained from NFOH. The calculated area under the curve (AUC 0-∞) showed that the exposure to the parental drug was fairly the same (844.79 vs 566.44) for NF and NF obtained from the prodrug administration. The tendency to higher NF's mean residence time (MRT) as observed in the prodrug administration (956.1 min vs 496.3 min) guarantees longer time for the action of the drug and it allows the expansion of the administration intervals. These findings, added with the beneficial characteristics of the prodrug encourage new efficacy tests towards the clinical use of NFOH. ©2013 Bentham Science Publishers. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013-01-01 2022-04-29T07:13:15Z 2022-04-29T07:13:15Z |
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 |
http://dx.doi.org/10.2174/18723128112069990013 Drug Metabolism Letters, v. 7, n. 1, p. 58-64, 2013. 1872-3128 http://hdl.handle.net/11449/227425 10.2174/18723128112069990013 2-s2.0-84891879595 |
url |
http://dx.doi.org/10.2174/18723128112069990013 http://hdl.handle.net/11449/227425 |
identifier_str_mv |
Drug Metabolism Letters, v. 7, n. 1, p. 58-64, 2013. 1872-3128 10.2174/18723128112069990013 2-s2.0-84891879595 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Drug Metabolism Letters |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
58-64 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128314371473408 |