Theophylline versus aminophylline in rectal administration

This study was undertaken to compare the bioavailability and the in vitro release rates of theophylline from suppositories containing either theophylline or aminophylline. The absorption of theophylline from solution and from freshly prepared suppositories formulated with Suppocire and containing anhydrous theophylline 250 mg or aminophylline 300 mg was investigated in six healthy volunteers in a blind crossover design experiment. Venous blood samples were collected before drug administration and at 1, 2, 4, 6 and 8 h afterwards. Theophylline serum levels were measured spectrophotometrically. The pharmacokinetic parameters obtained: Cmax 6.7 and 5.4 micrograms ml-1, tmax 2 h, and F8h 0.79 and 0.83 for theophylline and aminophylline, respectively, show that the two formulations are almost bioequivalent, with a slightly higher Cmax for theophylline. The in vitro release rate of theophylline from freshly prepared formulations was, however, higher (4.8 mg min-1) from aminophylline suppositories relative to those containing theophylline (2.9 mg min-1). This lack of correlation between the in vitro and in vivo results is explained by the different drug thermodynamic activities in the processes of release and membrane penetration. Thus, a better water-solubility does not automatically point to a better rectal bioavailability. The release rate of aminophylline suppositories tested after 1-year storage at room temperature dropped from 4.8 to 0.5 mg min-1. The bioequivalence of theophylline and aminophylline freshly prepared suppositories and the stability problems associated with fatty-base aminophylline suppositories indicate that the choice of ethylenediamine derivative of theophylline is an empirical development, theoretically unjustified, and must be replaced by theophylline reformulations.