ISOLATED PERFUSED RABBIT LUNG AS A MODEL FOR INTRAVASCULAR AND INTRA-BRONCHIAL ADMINISTRATION OF BRONCHODILATOR DRUGS .2. ISOPROTERENOL PRODRUGS

Isoproterenol is a .beta.-adrenergic agonist which is often employed in the treatment of bronchial asthma. The pulmonary disposition of 2 diester prodrugs of isoproterenol (di-p-toluoylisoproterenol and dipivaloylisoproterenol) was studied in the isolated perfused rabbit lung preparation. High-pressure liquid chromatographic methods were developed to measure diester, monoester, isoproterenol and 3-O-methylisoproterenol from a single 1-ml perfusate sample. The prodrugs were administered directly into the circulating perfusion medium and by endotracheal instillation. Perfusate concentrations of diester, monoester, isoproterenol and 3-O-methylisoproterenol were measured for 180 min. The diesters were rapidly eliminated from the perfusate with a subsequent increase in monoester concentrations. Isoproterenol levels were observed within minutes of prodrug administration, peaked at 60-80 min, and declined slowly thereafter. The prodrugs were rapidly absorbed following endotracheal administration with 30-50% of the diester being metabolized with 30-50% of the diester being metabolized during the first pass through the lung.