RT Journal Article SR Electronic T1 CYP3A INDUCTION BY N-HYDROXYFORMAMIDE TUMOR NECROSIS FACTOR-α CONVERTING ENZYME/MATRIX METALLOPROTEINASE INHIBITORS: USE OF A PREGNANE X RECEPTOR ACTIVATION ASSAY AND PRIMARY HEPATOCYTE CULTURE FOR ASSESSING INDUCTION POTENTIAL IN HUMANS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 870 OP 877 DO 10.1124/dmd.31.7.870 VO 31 IS 7 A1 Timothy K. Tippin A1 Geraldine Hamilton A1 Linda Moore A1 Elizabeth J. Beaudet A1 Summer Jolley A1 Thomas A. Brodie A1 Robert C. Andrews A1 J. David Becherer A1 Darryl L. McDougald A1 Michael D. Gaul A1 Debie J. Hoivik A1 Kathy Mellon-Kusibab A1 Jurgen Lehmann A1 Steven Kliewer A1 Steven Novick A1 Ron Laethem A1 Zhiyang Zhao A1 Edward L. LeCluyse YR 2003 UL http://dmd.aspetjournals.org/content/31/7/870.abstract AB A series of N-hydroxyformamide tumor necrosis factor-α 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 μM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 μM. 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. The American Society for Pharmacology and Experimental Therapeutics