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Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C.

Summary of "Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C."


PURPOSE:
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.
CONCLUSION:
Weekly administration of PEG-IFN alfa-2b to subjects with chronic hepatitis C increased CYP2C8/9 and CYP2D6 activity in some individuals.

Affiliation

Schering-Plough Research Institute, K15-22745 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA, samir.gupta@spcorp.com.

Journal Details

This article was published in the following journal.

Name: European journal of clinical pharmacology
ISSN: 1432-1041
Pages:

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Medical and Biotech [MESH] Definitions

A recombinant alfa interferon consisting of 165 amino acids with arginine at positions 23 and 34. It is used extensively as an antiviral and antineoplastic agent.

A recombinant alfa interferon consisting of 165 amino acids with lysine at position 23 and histidine at position 34. It is used extensively as an antiviral and antineoplastic agent.

A recombinant alfa interferon consisting of 165 amino acid residues with arginine in position 23 and histidine in position 34. It is used extensively as an antiviral and antineoplastic agent.

Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.

Specific molecular sites or structures on or in cells with which interferons react or to which they bind in order to modify the function of the cells. Interferons exert their pleiotropic effects through two different receptors. alpha- and beta-interferon crossreact with common receptors, while gamma-interferon initiates its biological effects through its own specific receptor system.

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