Cargando…

Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug

N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupro...

Descripción completa

Detalles Bibliográficos
Autores principales: O’Byrne, Paul Matthew, williams, Robert, walsh, John J., Gilmer, John F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078515/
https://www.ncbi.nlm.nih.gov/pubmed/24878537
http://dx.doi.org/10.3390/ph7060676
_version_ 1782323748747083776
author O’Byrne, Paul Matthew
williams, Robert
walsh, John J.
Gilmer, John F.
author_facet O’Byrne, Paul Matthew
williams, Robert
walsh, John J.
Gilmer, John F.
author_sort O’Byrne, Paul Matthew
collection PubMed
description N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans.
format Online
Article
Text
id pubmed-4078515
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-40785152014-07-02 Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug O’Byrne, Paul Matthew williams, Robert walsh, John J. Gilmer, John F. Pharmaceuticals (Basel) Article N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans. MDPI 2014-05-28 /pmc/articles/PMC4078515/ /pubmed/24878537 http://dx.doi.org/10.3390/ph7060676 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
O’Byrne, Paul Matthew
williams, Robert
walsh, John J.
Gilmer, John F.
Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title_full Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title_fullStr Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title_full_unstemmed Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title_short Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug
title_sort part two: evaluation of n-methylbupropion as a potential bupropion prodrug
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078515/
https://www.ncbi.nlm.nih.gov/pubmed/24878537
http://dx.doi.org/10.3390/ph7060676
work_keys_str_mv AT obyrnepaulmatthew parttwoevaluationofnmethylbupropionasapotentialbupropionprodrug
AT williamsrobert parttwoevaluationofnmethylbupropionasapotentialbupropionprodrug
AT walshjohnj parttwoevaluationofnmethylbupropionasapotentialbupropionprodrug
AT gilmerjohnf parttwoevaluationofnmethylbupropionasapotentialbupropionprodrug