Drug interactions. I. Effects of repeated administration of combined analgesic on its pharmacological activity and on hepatic drug-metabolizing enzyme activities in mice.

Abstract

In order to elucidate the interactions of the components of an aminopyrine (28.9 mg)-phenacetin (57.8 mg)-phenobarbital (13.3 mg) preparation on repeated administration (100 mg/kg of body weight) to mice, the analgesic activity of the preparation, the hepatic drug-metabolizing enzyme activities and the plasma concentrations of phenobarbital, phenacetin and acetaminophen in mice dosed repeatedly for 7 days were estimated in comparison with a single dose group. The analgesic activity was significantly decreased and the liver drug-metabolizing enzyme activities were markedly enhanced after the repeated treatment as compared with the results obtained following a single dose. The plasma levels of phenacetin were markedly lower at both 45 and 90 min in the repeated dose group, while the levels of acetaminophen and its glucuronide were higher in mice dosed repeatedly than in the single dose group 45 min after intraperitoneal injection, but lower after 90 min. The plasma concentrations of phenobarbital 45 and 90 min after the combined drug were not significantly different in the single and repeated dose groups. When the induction rate of the drug-metabolizing enzymes by the combined drug was compared with that by phenobarbital alone, there was a clear-cut correlation (r=0.986 for repeated dosing and r=0.985 for a single dose). This strongly suggests that phenobarbital in the combined analgesic induced metabolic inactivation of the other component drugs without significant enhancement of its own metabolism, while aminopyrine and phenacetin had no such effect.