title: Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C.
abstract: OBJECTIVE
  To examine the effect of pegylated interferon (PEG-IFN) alfa-2b on the activity of major drug-metabolizing enzymes.
  
  
  METHODS
  This nonrandomized, open-label, multiple-dose study examined the effects of PEG-IFN alfa-2b on the activity of CYP450 1A2, 2 C8/9, 2D6, and 3A4 enzymes and N-acetyltransferase in subjects with chronic hepatitis C. Eligible subjects received PEG-IFN alfa-2b 1.5 μg/kg subcutaneously once weekly for 4 weeks (days 3, 10, 17, and 24). Oral probe substrates (dextromethorphan hydrobromide 45 mg, caffeine 200 mg, tolbutamide 500 mg, and dapsone 100 mg) were administered after a 10-h fast on days 1 and 25. Midazolam 4 mg was administered orally on days 2 and 26. Enzyme activity for each CYP450 isozyme and for N-acetyltransferase was estimated based on the ratios of the observed concentrations of the substrates and metabolites in plasma or urine samples.
  
  
  RESULTS
  Twenty-six subjects enrolled in the study. Mean age was 44.3 years, mean weight was 78.9 kg, and mean body mass index was 26.3 kg/m(2). Multiple doses of PEG-IFN alfa-2b inhibited CYP1A2 activity to a limited extent (point estimate = 84.2%, 90% confidence interval [CI] 79-90), increased CYP2C8/9 activity to a limited extent (point estimate = 127.6%, 90% CI 115-142), increased CYP2D6 activity (point estimate = 167%, 90% CI 125-223), and had no effect on the activity of CYP3A4 or N-acetyltransferase.
  
  
  CONCLUSIONS
  Weekly administration of PEG-IFN alfa-2b to subjects with chronic hepatitis C increased CYP2C8/9 and CYP2D6 activity in some individuals.
authors.affiliation: Schering-Plough Research Institute, K15-22745 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. samir.gupta@spcorp.com
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Karen
authors.initials: K
authors.lastname: Kolz
authors.forename: David L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D000328:Adult; D051046:Amino-Acid N-Acetyltransferase / Q000097:blood / Q000378:metabolism; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism / Q000652:urine; D019388:Cytochrome P-450 CYP1A2 / Q000097:blood / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008658:Inactivation, Metabolic; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D051046:Amino-Acid N-Acetyltransferase; C417083:peginterferon alfa-2b