CYP3A induction by N-hydroxyformamide tumor necrosis factor-alpha converting enzyme/matrix metalloproteinase inhibitors use of a pregname X receptor activation assay and primary hepatocyte culture for assessing induction potential in humans

Drug Metab Dispos. 2003 Jul;31(7):870-7. doi: 10.1124/dmd.31.7.870.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Administration, Oral
  • Amides / administration & dosage
  • Amides / pharmacokinetics
  • Aminopyridines / administration & dosage
  • Aminopyridines / blood
  • Aminopyridines / pharmacokinetics
  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Aryl Hydrocarbon Hydroxylases / drug effects
  • Cell Culture Techniques
  • Cytochrome P-450 CYP3A
  • Dipeptides / administration & dosage
  • Dipeptides / blood
  • Dipeptides / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Drug Evaluation
  • Drug Evaluation, Preclinical
  • Enzyme Induction
  • Formamides / chemistry
  • Formamides / pharmacology*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Male
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / administration & dosage
  • Matrix Metalloproteinases / pharmacokinetics
  • Metalloendopeptidases / antagonists & inhibitors*
  • Oxidoreductases, N-Demethylating / biosynthesis*
  • Oxidoreductases, N-Demethylating / drug effects
  • Pregnane X Receptor
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / drug effects
  • Receptors, Steroid / metabolism*
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacokinetics

Substances

  • (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
  • Amides
  • Aminopyridines
  • Dipeptides
  • Formamides
  • GW 3333
  • Matrix Metalloproteinase Inhibitors
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Thiazoles
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • ADAM Proteins
  • Matrix Metalloproteinases
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, rat