A model to describe myocardial drug disposition in the dog

A model, employing open-chested, anesthetized dogs, was developed to facilitate the study of myocardial drug disposition. Propranolol was employed as a model compound for initial investigation. Propranolol was administered as either a single i.v. bolus of 0.5 mg/kg or by a stepwise infusion protocol employing three rates: 2.6, 6.5 and 12.0 micrograms/kg/min. Blood and myocardial biopsy samples were obtained at specified times and the concentration of propranolol in tissue homogenates and plasma was determined by a high-pressure liquid chromotographic procedure. The concentration-time data obtained from the i.v. bolus studies were fitted to a three-compartment model where one of the compartments represented the myocardium. The model predicts that plasma and myocardial concentrations achieve distribution equilibrium within 2 min after administration. The myocardial-to-plasma concentration ratios ranged from 6.2 to 20.3 and were constant with time for each dog. The myocardial-to-plasma concentration ratios also remained constant during the infusion protocol, indicating linear accumulation up to myocardial concentrations of 6.7 micrograms/ml. To assess regional myocardial concentration differences, the concentration of drug in the right atrium was compared with the concentration of drug in the right atrium was compared with the concentration in the left ventricle at the end of the infusion protocol. The concentrations were not significantly different. The model developed will be used to study the myocardial disposition of several antiarrhythmic drugs and the factors which affect their rate and extent of accumulation.