Caffeine-phenacetin interaction in the rat: effects on absorption, metabolism and locomotor activity

Abstract The interactive effects of caffeine and phenacetin on the locomotor activity of the DA rat involved changes in absorption and metabolism as well as effects possibly exerted at the cns level. Phenacetin initially retarded the absorption of caffeine when coadministered by gavage but not when caffeine was given intraperitoneally and phenacetin orally. Phenacetin also increased the time for the plasma/caffeine concentration to peak, increased its peak concentration and prolonged its presence in the plasma. Urinary excretion patterns, suggested a blockade of the N-demethylation of caffeine by phenacetin. In contrast, caffeine had only a minor influence on the absorption and metabolism of phenacetin. The locomotor effects of the caffeine-phenacetin combination reflected the absorptive and metabolic interactions which occurred. Caffeine-induced hyperactivity was initially masked by phenacetin in a dose-dependent manner but after 2 h, when the plasma phenacetin concentrations were much lower, its retarding influence on caffeine metabolism became apparent and hyperactivity consequent upon an elevated plasma caffeine concentration was seen. Phenacetin also antagonized the hyperactive effects of theophylline and of (+)-amphetamine.