Abstract
A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Administration, Oral
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Amides / administration & dosage
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Amides / pharmacokinetics
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Aminopyridines / administration & dosage
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Aminopyridines / blood
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Aminopyridines / pharmacokinetics
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Animals
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Aryl Hydrocarbon Hydroxylases / biosynthesis*
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Aryl Hydrocarbon Hydroxylases / drug effects
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Cell Culture Techniques
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Cytochrome P-450 CYP3A
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Dipeptides / administration & dosage
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Dipeptides / blood
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Dipeptides / pharmacokinetics
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Dose-Response Relationship, Drug
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Drug Evaluation
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Drug Evaluation, Preclinical
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Enzyme Induction
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Formamides / chemistry
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Formamides / pharmacology*
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Humans
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Male
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / administration & dosage
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Matrix Metalloproteinases / pharmacokinetics
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Metalloendopeptidases / antagonists & inhibitors*
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Oxidoreductases, N-Demethylating / biosynthesis*
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Oxidoreductases, N-Demethylating / drug effects
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Pregnane X Receptor
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / drug effects
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Steroid / drug effects
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Receptors, Steroid / metabolism*
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Thiazoles / administration & dosage
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Thiazoles / pharmacokinetics
Substances
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(2R,3S)-6,6,6-trifluoro-3-(formyl(hydroxy)amino)-2-isobutyl-N-((1S,2R)-2-methoxy-1-((1,3-thiazol-2-ylamino)carbonyl)propyl)hexanamide
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Amides
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Aminopyridines
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Dipeptides
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Formamides
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GW 3333
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Matrix Metalloproteinase Inhibitors
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Pregnane X Receptor
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Thiazoles
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP3A
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Oxidoreductases, N-Demethylating
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ADAM Proteins
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Matrix Metalloproteinases
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Metalloendopeptidases
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, rat