Effect of caffeine on circulating theophylline levels in beagle dogs

The pharmacokinetic interactions of caffeine with theophylline were examined in two beagle dogs by administering 100 mg of aminophylline intravenously, 3 weeks before and immediately after repeated oral doses of caffeine. Serial plasma samples were analyzed for caffeine and theophylline simultaneously by high-performance liquid chromatography. Upon multiple oral dosing, 100 mg every 12 hr for 7 days, the caffeine half-life increased slightly in one dog but decreased in the other. As predicted from single-dose data, caffeine accumulation in plasma after repeated doses was slight, while plasma levels of the N-demethylated metabolite, theophylline, rose to about three times the initial values. After rapid intravenous doses of aminophylline, the theophylline half-life was 5-7 hr, which decreased slightly when the drug was administered concomitantly with caffeine during steady state of caffeine. The theophylline volume of distribution (0.75 liter/kg) was unaffected by caffeine. On the other hand, an acute aminophylline injection prolonged the elimination half-life and increased the apparent volume of distribution of caffeine, causing little overall change in its plasma clearance. The results suggested that interactions between theophylline and caffeine may be attributed to changes in drug distribution and drug elimination characteristics.