Pharmacokinetics and Pharmacodynamics of Theophylline in Ruminating Calves

Abstract

This study was undertaken to investigate the potential use of theophylline as an ancillary therapeutic agent in the treatment of bovine respiratory disease. Results from this study indicate that the central disposition of theophylline in healthy ruminating calves is best described by a first-order two-compartment open pharmacokinetic model. The drug has a mean elimination half-life of 6.4 hours and a mean distribution half-life of 22 minutes. Total body clearance averages 91 ml/kg/hr. The mean apparent specific volumes of distribution for ${\rm V\sb{c}}$, ${\rm V\sb{z}}$ and ${\rm V\sb{66}}$ are 0.502, 0.870, and 0.815 l/kg, respectively.

Theophylline is readily absorbed in the ruminating calf after oral administration with a mean bioavailability (F) of 0.93. The plasma concentrations following oral dosing peak in approximately 5-6 hours with a mean absorption half-life of 3.7 hours.

The drug is extensively absorbed across the rumen epithelium (mean 81%). Atropine-induced gastrointestinal hypomotility significantly slows but does not prevent absorption of the drug. Intestinal absorption is both rapid and near complete. In a multiple dose trial healthy animals responded as predicted while diseased animals had higher than expected plasma concentrations.

Too few animals were available to draw significant conclusions regarding the therapeutic plasma concentration of theophylline in cattle. Still, preliminary data suggest that theophylline has a poor ability to reverse an induced bronchoconstriction but is efficacious in preventing bronchoconstriction. The therapeutic window for theophylline in cattle probably exists between 11.5 and 26.8 $\mu$g/ml.

Based on the evidence provided here, it is suggested that theophylline can be used as an ancillary therapeutic agent in bovine respiratory disease but is not without risk. Theophylline should be used only by a trained veterinarian knowledgeable of the drug and its toxic potential. The suggested oral dose of theophylline at 28 mg/kg of body weight once daily should be tailored to each individual situation. Twice daily oral dosing at 20 mg/kg should reduce the plasma peak:trough ratio and provide plasma concentrations more consistently within the human therapeutic range of 10-20 $\mu$g/ml. Even then, due to changes which may be age or disease-related, therapeutic drug monitoring would be prudent.