Theophylline bioavailability following chronic dosing of an elixir and two solid dosage forms

Abstract

Theophylline bioavailability following chronic dosing of an elixir and two commercial tablet formulations (I and II) relative to an acute dose of elixir was evaluated in healthy volunteers. Both tablet formulations contained ephedrine. In addition, Tablet I contained hydroxyzine hydrochloride, and Tablet II contained phenobarbital. The mean area under the serum concentration-time curve (AUC) calculated either from time 0 leads to infinity for a single dose or over one dosing interval after repetitive doses was the highest after chronic administration of the elixir. The AUC after chronic elixir, in fact, was statistically different from the values after acute elixir (p less than 0.05) and Tablet II (p less than 0.05). There was, however, a large variation in the elimination half-life among the four theophylline treatments. The mean t 1/2 was the longest after chronic elixir followed by Tablet I, Tablet II, and acute elixir. The AUC values for the four treatments, when corrected for differences in t 1/2, were no longer significantly different, indicating that the extent of theophylline absorption was essentially the same from all three tested products. The time to peak and the peak serum concentration also did not differ among treatments. The prolongation in t 1/2 following chronic treatment with the elixir and its subsequent shortening during tablet administration suggest an initial inhibition followed by induction of theophylline metabolism. The changes may be due to the prolonged treatment with theophylline itself or the other drug ingredients in the dosage form.