Dose-dependent elimination of theophylline in rats

Abstract

1. The effect of different doses on the rate of metabolism of theophylline in rats was investigated. 2. After doses of 52 or 115 mg/kg, the initial concn. decayed according to a first-order process with an apparent half-life of about four hours. However, after four to eight hours the slope of the curves declined, resulting in elimination half-lives of about 70 min. Similar half-lives of 70 min were also found after doses of 6 or 11 mg/kg. 3. The AUC increased disproportionately with dose, indicating capacity-limited elimination. 4. No differences were observed in capacity-limited elimination of the two major metabolites of theophylline: the ratio between the amounts of 1, 3-dimethyluric acid and 1-methyluric acid formed was independent of the dose of theophylline. 5. The initial apparent first-order decay after higher doses resulted from a combination of capacity-limited metabolism and compensatory increased diuresis of unchanged theophylline. 6. It is concluded that linear pharmacokinetics of theophylline in rats apply only to doses not exceeding 10 mg/kg.