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CYP3A INDUCTION BY N-HYDROXYFORMAMIDE TUMOR NECROSIS FACTOR- CONVERTING ENZYME/MATRIX METALLOPROTEINASE INHIBITORS: USE OF A PREGNANE X RECEPTOR ACTIVATION ASSAY AND PRIMARY HEPATOCYTE CULTURE FOR ASSESSING INDUCTION POTENTIAL IN HUMANS

GlaxoSmithKline, Research Triangle Park, North Carolina (T.K.T., L.M., E.J.B., T.A.B., R.C.A., J.D.B., D.L.M., M.D.G., D.J.H., K.M.-K., J.L., S.K., S.N., R.L., Z.Z.); and Division of Drug Delivery and Disposition, University of North Carolina School of Pharmacy, Chapel Hill, North Carolina (T.K.T., G.H., S.J., E.L.L.)

A series of N-hydroxyformamide tumor necrosis factor- 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.

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