Theophylline absorption and disposition in rabbits: oral, intravenous, and concentration-dependent kinetic studies

Theophylline pharmacokinetics following oral and intravenous administration were studied, and the absolute bioavailability of five commercially available products was determined using the rabbit as an in vivo model. Concentration-dependent clearance studies were performed by multiple constant-rate infusion and multiple bolus dose administration of aminophylline. Theophylline pharmacokinetics following the oral administration of these products obeyed the one-compartment open model adequately. However, the data obtained following rapid intravenous aminophylline administration in the rabbit fit either the one-compartment model (half-life = 2.8 hr and the volume of distribution = 4.4 hr and Vd(beta) = 0.708 liter/kg). There were no significant product-to-product differences in the time to peak (tmax), the rate constant of absorption (ka), or the percent of dose absorbed at 1 hr (F1); however, differences in the absolute bioavailability (F), dose-normalized peak serum concentration (Cmax(n)), and percent of dose absorbed at 6 hr (F6) were significant. There was no evidence of concentration-dependent clearance for theophylline in the rabbit in the serum concentration range studied, but the results of the multiple constant-rate infusion study suggest that total clearance decreases at higher serum theophylline concentrations.