Interferon suppresses erythromycin metabolism in rats and human subjects

Authors

  • Philip I. Craig,

    1. Department of Medicine, University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia
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  • Michael Tapner,

    1. Department of Medicine, University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia
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  • Geoffrey C. Farrell

    Associate Professor, Corresponding author
    1. Department of Medicine, University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia
    • Department of Medicine, Westmead Hospital, Westmead NSW 2145, Australia
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Abstract

Interferon down-regulates expression of cytochrome P-450 3A in male rats. This study explored the hypothesis that interferon therefore decreases the metabolism of drugs catalyzed by cytochrome P-450 3A. Initial experiments in male rats used microsomal erythromycin N-demethylase activity as a probe for cytochrome P-450 3A catalytic activity. After administration of rat interferon-γ, erythromycin metabolism was impaired (53% of control; p < 0.01). This change correlated with the decline in cytochrome P-450 3A–dependent androstenedione 6β-hydroxylase activity, indicating that the decrease in erythromycin N-demethylase activity could be attributed to interferon-mediated suppression of cytochrome P-450 3A. We then used the [14C]N-methyl erythromycin breath test to assess the activity of hepatic cytochrome P-450 3A in rats and human subjects before and after a single dose of interferon. In rats, rat interferon-γ decreased erythromycin metabolism to 57% of control (p < 0.005). In the human study, six patients with chronic active hepatitis C and four healthy controls were examined 20 to 26 hr after receiving a subcutaneous injection of human interferon-α2b. Interferon produced a small decrease (median = 15%; range = 3% to 35%) in erythromycin metabolism (p < 0.05), as determined by 2-hr excretion of 14CO2 in the breath. Thus interferon-mediated suppression of cytochrome P-450 3A is less strong in human subjects than in male rats. Comparison of our data about the effect of interferon on cytochrome P-450 3A activity with earlier observations of a major impairment of theophylline clearance in human beings suggests that in human subjects interferon may have a more important effect on other drug-metabolizing enzymes, such as those of the cytochrome P-450 1A subfamily. However, interferon may produce clinically relevant impairment in the elimination of drugs that are substrates for cytochrome P-450 3A, should such agents have a narrow therapeutic index. (HEPATOLOGY 1993;17:230–235.)

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