Drug absorption from inhalation aerosols administered by positive-pressure ventilation. I: Administration of a characterized, solid disodium fluorescein aerosol under a controlled respiratory regime to the beagle dog.
An apparatus and novel method is described for administration of well-characterized inhalation aerosols, under strictly controlled respiratory regimes, direct to the respiratory tract (RT) of the beagle dog by positive-pressure ventilation. The method enables the study of systemic absorption kinetics of compounds delivered as inhalation aerosols as a function of the aerosol particle size and respiratory variables provided their intrinsic pharmacokinetics are linear. Aerosol characteristics are determined by sampling the aerosol at a point close to its entry to the endotracheally intubated animal. The chosen positive-pressure ventilatory regime, which is monitored as airway pressure and exhaled volume versus time, can be held constant for the aerosol administration period. The methodology is illustrated by administration of a solid polydispersed aerosol of disodium fluorescein. Resultant plasma concentrations (C) were determined as a function of time by sampling from an indwelling venous cannula. The pharmacokinetic analysis of resultant C versus time data, together with that from an intravenous control experiment, is described to determine the amount absorbed as a function of time. Following aerosol administration according to the chosen respiratory regime, fluorescein was rapidly absorbed from the RT. The methodology will enable systematic variation of the particle size and positive-pressure respiratory regime in order to determine effects on drug absorption kinetics.