Interferon suppresses erythromycin metabolism in rats and human subjects

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.) Show more