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Abstract
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 additionminimizes any cytotoxic effects, whichmay compromise interpretation of the experimental data.
Original language | English |
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Pages (from-to) | 479-488 |
Number of pages | 10 |
Journal | Biochemical Journal |
Volume | 465 |
Issue number | 3 |
Early online date | 7 Nov 2014 |
DOIs | |
Publication status | Published - Feb 2015 |
Keywords
- Conditional inducible deletion
- Cytochrome P450 oxidoreductase
- Drug bioavailability
- Gut
- Liver
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
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Dive into the research topics of 'Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability'. Together they form a unique fingerprint.Projects
- 1 Finished
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Molecular and Pharmacological Characterisation of Pathways Which Determine the Sensitivity of Cells to Anti-Cancer Drugs and Chemopreventive Agents
Henderson, C. (Investigator) & Wolf, R. (Investigator)
1/07/11 → 31/07/17
Project: Research
Profiles
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Wolf, Roland
- Cancer Research - Professor (Teaching and Research) of Molecular Pharmacology
Person: Academic