Abstract
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.
Footnotes
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↵1 Abbreviations used are: TACE, tumor necrosis factor-α converting enzyme; MMP, matrix metalloproteinase; GW3333, (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide; PCN, pregnenalone16α-carbonitrile; PXR, pregnane X receptor; HPLC, high-performance liquid chromatography; MS, mass spectrometry; DMSO, dimethyl sulfoxide; AUC, area under the plasma concentration-time curve; ANOVA, analysis of variance; h, human; GI4023, (2R)-N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-2-{(1S)-1-[formyl(hydroxy)amino]ethyl}-5-phenylpentanamide; GW6495, (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; r, rat; P450, cytochrome P450; LC/MS-MS, liquid chromatography/tandem mass spectrometry.
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This work was financed by GlaxoSmithKline, Research Triangle Park, North Carolina.
- Received November 13, 2002.
- Accepted March 24, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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