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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2014
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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 |
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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 |
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