Depression of Drug-metabolizing Activity in the Human Liver by Interferon-β

Abstract

The depressant effect of interferon beta on drug-metabolizing activity in the human liver was investigated. Seven patients with chronic hepatitis C were treated with interferon beta at doses of 3 x 10(6) to 9 x 10(6) IU/day for 8 wk. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Theophylline pharmacokinetics were also examined before and after interferon treatment. Interferon beta treatment reduced the activities of both O-dealkylases from 6.0 (100%) to 3.2 (53%) nmol/gm liver per minute and from 1.9 (100%) to 1.1 (58%) nmol/gm liver per minute, respectively (p < 0.05). The total body clearance of theophylline was also decreased (from 0.76 to 0.56 ml/kg/min; p < 0.05), and its elimination half-life was increased (from 8.4 to 11.7 hr; p < 0.05); however, the volume of distribution was not significantly affected. The magnitude of the decreases in enzyme activities and in theophylline clearance varied widely in individual patients and did not correlate with the dose of interferon administered. This study provides the first direct evidence that interferon beta can depress the activity of drug-metabolizing enzymes in the human liver.

Immunological Response as a Source to Variability in Drug Metabolism and Transport

“…Williams et al (1987) reported already in 1987 that 1 day after a single intramuscular injection of IFN-α in five patients with chronic hepatitis B and four healthy volunteers, clearance of the CYP1A2 substrate theophylline was significantly reduced (30–80%). A 26% reduction in clearance of theophylline was also observed in patients with hepatitis C after IFN-β treatment, with a corresponding increase in terminal half-life of about 40% (Okuno et al, 1993). Additionally IFN-α administration in patients with hepatitis B has been shown to cause a minor decrease of erythromycin metabolism (15%), as determined by ERMBT (Craig et al, 1993), and patients monitored on warfarin needed a dose reduction when IFN-α-2b and IFN-β were given (Adachi et al, 1995).…”

Liver resistance to CCl4-induced injury after stimulation of macrophages with various preparations

“…In this case, interferons [10], interleukin-I [13], and tumor necrosis factor [9] secreted by activated MP act as inhibitory monokines. The amount and type of synthesized products depend on the nature, dose, molecular weight, physical properties, chemical composition, and structure of the stimulating substance, as well as on the reciprocal regulation by MP mediators.…”

Modulation of hepatic mRNA levels after administration of lipopolysaccharide and diphtheria and tetanus toxoids and pertussis vaccine adsorbed (dtp vaccine) to mice

“…We have shown that administration of TNF, IL-1, IFN-y and IL-2 results in reduced levels of cytochromes P-450 in a dose-dependent manner (30,33). Furthermore, clinical studies with these agents have reported liver toxicity, including altered drug clearance, as a side effect (34). This could be a direct consequence of altered enzymatic activities.…”