title: 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.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Department, Metabolic and Viral Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Tim.K.Tippin@gsk.com
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Tippin
authors.forename: Geraldine
authors.initials: G
authors.lastname: Hamilton
authors.forename: Linda
authors.initials: L
authors.lastname: Moore
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Beaudet
authors.forename: Summer
authors.initials: S
authors.lastname: Jolley
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brodie
authors.forename: Robert C
authors.initials: RC
authors.lastname: Andrews
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: Darryl L
authors.initials: DL
authors.lastname: McDougald
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gaul
authors.forename: Debie J
authors.initials: DJ
authors.lastname: Hoivik
authors.forename: Kathy
authors.initials: K
authors.lastname: Mellon-Kusibab
authors.forename: Jurgen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Steven
authors.initials: S
authors.lastname: Kliewer
authors.forename: Steven
authors.initials: S
authors.lastname: Novick
authors.forename: Ron
authors.initials: R
authors.lastname: Laethem
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000187:drug effects; D018929:Cell Culture Techniques; D051544:Cytochrome P-450 CYP3A; D004151:Dipeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D005559:Formamides / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000008:administration & dosage / Q000493:pharmacokinetics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000187:drug effects; D000077297:Pregnane X Receptor; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C482240:(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; D000577:Amides; D000631:Aminopyridines; D004151:Dipeptides; D005559:Formamides; C434456:GW 3333; D061965:Matrix Metalloproteinase Inhibitors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013844:Thiazoles; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat