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In vitro metabolism and in vivo pharmacokinetics of quinoline 3-carboxamide derivatives in various species

Tuvesson, Helen LU ; Hallin, I; Ellman, M; Sparre, B; Gunnarsson, PO and Seidegard, J (2005) In Xenobiotica 35(3). p.293-304
Abstract
The metabolism of a group of quinoline 3-carboxamide derivatives was evaluated in liver microsomes from various species. In addition, metabolism data were compared with in vivo pharmacokinetics in the mouse. The studied compounds were metabolized by cytochrome P450 enzymes. Microsomal clearance was low and seemed independent of a substituent in the quinoline moiety, whereas clearance was enhanced when an ethyl group replaced the methyl group at the carboxamide position. A similar metabolism with hydroxylated and dealkylated metabolites was found in the various species, with quantitative differences due to substituent. As predicted from the in vitro studies, in vivo pharmacokinetics showed low clearance and thus high exposure of the parent... (More)
The metabolism of a group of quinoline 3-carboxamide derivatives was evaluated in liver microsomes from various species. In addition, metabolism data were compared with in vivo pharmacokinetics in the mouse. The studied compounds were metabolized by cytochrome P450 enzymes. Microsomal clearance was low and seemed independent of a substituent in the quinoline moiety, whereas clearance was enhanced when an ethyl group replaced the methyl group at the carboxamide position. A similar metabolism with hydroxylated and dealkylated metabolites was found in the various species, with quantitative differences due to substituent. As predicted from the in vitro studies, in vivo pharmacokinetics showed low clearance and thus high exposure of the parent compounds in the mouse. The therapeutic effect seen in the acute EAE mouse model for these related compounds seems dependent on the high exposure of parent compound rather than formation of any potentially active metabolites. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
quinoline 3-carboxamides, metabolism, pharmacokinetics
in
Xenobiotica
volume
35
issue
3
pages
293 - 304
publisher
Taylor & Francis
external identifiers
  • pmid:16019952
  • wos:000229621800006
  • scopus:20144376334
ISSN
0049-8254
DOI
10.1080/00498250500066329
language
English
LU publication?
yes
id
0398abcc-766c-4d04-b108-8b8fc435a858 (old id 236372)
date added to LUP
2007-08-15 16:10:44
date last changed
2017-08-27 05:23:38
@article{0398abcc-766c-4d04-b108-8b8fc435a858,
  abstract     = {The metabolism of a group of quinoline 3-carboxamide derivatives was evaluated in liver microsomes from various species. In addition, metabolism data were compared with in vivo pharmacokinetics in the mouse. The studied compounds were metabolized by cytochrome P450 enzymes. Microsomal clearance was low and seemed independent of a substituent in the quinoline moiety, whereas clearance was enhanced when an ethyl group replaced the methyl group at the carboxamide position. A similar metabolism with hydroxylated and dealkylated metabolites was found in the various species, with quantitative differences due to substituent. As predicted from the in vitro studies, in vivo pharmacokinetics showed low clearance and thus high exposure of the parent compounds in the mouse. The therapeutic effect seen in the acute EAE mouse model for these related compounds seems dependent on the high exposure of parent compound rather than formation of any potentially active metabolites.},
  author       = {Tuvesson, Helen and Hallin, I and Ellman, M and Sparre, B and Gunnarsson, PO and Seidegard, J},
  issn         = {0049-8254},
  keyword      = {quinoline 3-carboxamides,metabolism,pharmacokinetics},
  language     = {eng},
  number       = {3},
  pages        = {293--304},
  publisher    = {Taylor & Francis},
  series       = {Xenobiotica},
  title        = {In vitro metabolism and in vivo pharmacokinetics of quinoline 3-carboxamide derivatives in various species},
  url          = {http://dx.doi.org/10.1080/00498250500066329},
  volume       = {35},
  year         = {2005},
}