Theophylline: pharmacokinetics, metabolism and urinary excretion in dogs

The disposition of theophylline (aminophylline) administered either parenterally or orally to anesthetized dogs was studied. Pharmacokinetics of theophylline (8.2 mg/kg, n = 10) following intravenous administration could be analyzed by a two-compartment open model. The half-time (T1/2 beta) of theophylline was 5.63 +/- 0.83 hr, and the volume of distribution (Vd) was 0.73 +/- 0.04 l/kg. The elimination rate constant was 0.37 +/- 0.05 hr-1. Two metabolites of theophylline were isolated from urine and identified as 3-methyl xanthine (3-MX) and 1,3-dimethyl uric acid (1,3-DMU) by HPLC. The dogs excreted about 85% (n = 4) of the dose in urine in 24 hr. The majority (2/3) was excreted as changed theophylline, i.e., 3-MX 40.2 +/- 3.5% and 1,3-DMU 26.2 +/- 4.3%, while unchanged theophylline amounted to 18.2 +/- 2.4%. Absorption of theophylline (8.2 mg/kg, n = 5) administered intramuscularly was good as indicated by its high bioavailability (101.9 +/- 6.5%), but the value of bioavailability was low in oral administration (72.8 +/- 11.8%, n = 5). The percentage of protein binding (about 44%, n = 3-7) did not change by increasing the serum concentration (8.2-24.6 micrograms/ml).