Effect of the immunomodulator tilorone on antipyrine disposition in the rat.
A wide variety of immunomodulators, including the synthetic interferon inducer tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one), have been shown to inhibit cytochrome P-450-dependent drug metabolism in vitro. In an effort to determine if tilorone also inhibits drug metabolism in vivo, we examined the effect of this agent on the disposition of antipyrine in the rat. Administration of tilorone hydrochloride (50 mg X kg-1 X d-1) 4 d resulted in a 42% reduction in antipyrine clearance and a 71% increase in plasma half-life. Administration of a single dose of tilorone hydrochloride (50 mg/kg) 48 h prior to antipyrine was found to cause a similar alteration in antipyrine clearance and half-life. Both treatment regimens were also found to produce a substantial weight loss in the pretreated animals. Preliminary studies indicated that tilorone treatment reduced food and water consumption in the rat. Therefore, the effect of a 75% decrease in food and water consumption on antipyrine disposition was also examined. This magnitude of restriction had no detectable effect on antipyrine elimination. Thus, tilorone results in a substantial reduction of the in vivo metabolic clearance of antipyrine and appears to be a useful compound for studying the dynamic interaction between the drug metabolizing and immune systems in vivo.