Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine

Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.