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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.
