Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electr...

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Autores principales: Henderson, Colin J., McLaughlin, Lesley A., Osuna-Cabello, Maria, Taylor, Malcolm, Gilbert, Ian, McLaren, Aileen W., Wolf, C. Roland
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949133/
https://www.ncbi.nlm.nih.gov/pubmed/25377919
http://dx.doi.org/10.1042/BJ20140582
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author Henderson, Colin J.
McLaughlin, Lesley A.
Osuna-Cabello, Maria
Taylor, Malcolm
Gilbert, Ian
McLaren, Aileen W.
Wolf, C. Roland
author_facet Henderson, Colin J.
McLaughlin, Lesley A.
Osuna-Cabello, Maria
Taylor, Malcolm
Gilbert, Ian
McLaren, Aileen W.
Wolf, C. Roland
author_sort Henderson, Colin J.
collection PubMed
description The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs – paroxetine, midazolam, nelfinavir – and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.
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spelling pubmed-69491332020-01-08 Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability Henderson, Colin J. McLaughlin, Lesley A. Osuna-Cabello, Maria Taylor, Malcolm Gilbert, Ian McLaren, Aileen W. Wolf, C. Roland Biochem J Article The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs – paroxetine, midazolam, nelfinavir – and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data. 2015-02-01 /pmc/articles/PMC6949133/ /pubmed/25377919 http://dx.doi.org/10.1042/BJ20140582 Text en http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Henderson, Colin J.
McLaughlin, Lesley A.
Osuna-Cabello, Maria
Taylor, Malcolm
Gilbert, Ian
McLaren, Aileen W.
Wolf, C. Roland
Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title_full Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title_fullStr Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title_full_unstemmed Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title_short Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
title_sort application of a novel regulatable cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949133/
https://www.ncbi.nlm.nih.gov/pubmed/25377919
http://dx.doi.org/10.1042/BJ20140582
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