The bioavailability of theophylline from an extended-release formulation (Uni-Dur) intended for once-daily administration was assessed in a randomized, single-dose, five-way crossover study to determine the effects of food and breaking the tablet, and the bioequivalence of two dosage strengths. The five treatments given at 1-week intervals were (1) immediate-release theophylline (Slo-Phyllin) 5 x 100 mg to fasting subjects as a reference treatment; (2) sustained-release Uni-Dur 600-mg theophylline tablet to fasting subjects; (3) Uni-Dur 600-mg tablet after a high-fat meal; (4) Uni-Dur 600-mg dose administered as two half tablets to fasting subjects; and (5) Uni-Dur 400-mg tablet to fasting subjects. Serial blood samples were collected immediately before and for 57 hours after dosing. The mean relative extents of absorption for the four Uni-Dur treatments were not significantly different from Slo-Phyllin treatment or from each other (84.30 +/- 23.6%, 600 mg, fasting; 88.73 +/- 18.63%, 600 mg, fed; 93.65 +/- 19.67%, half tablet; and 92.87 +/- 19.5%, 400 mg, fasting). The maximum theophylline serum concentrations with Uni-Dur were significantly lower and the times to reach peak concentrations were significantly longer than with Slo-Phyllin. Differences noted among the four Uni-Dur treatments were as follows: the time to peak theophylline concentration was significantly longer in the fed state (17.09 hours) as were the times to 50% (11.73 hours) and 80% (18.46 hours) absorption compared with fasting (13.57 hours, 8.57 hours, and 14.07 hours, respectively). The Uni-Dur 400-mg treatment resulted in a significantly higher maximum theophylline serum concentration (6.64 mu g/mL) compared with the Uni-Dur 600-mg fasting treatment (5.33 mu g/mL); however, the correlation between in vivo and in vitro data supports the bioequivalence of the two strengths. This study shows that theophylline is slowly and consistently absorbed from the Uni-Dur 24-hour sustained-release form, and food or breaking the tablet does not alter the extent of absorption. Thus Uni-Dur potentially provides greater ease of administration and convenience for patients while maintaining therapeutic theophylline serum levels over the 24-hour dosing interval.