Liquid dose pulmonary instillation of gentamicin PulmoSpheres (R) formulations: Tissue distribution and pharmacokinetics in rabbits

Purpose. To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres((R)) formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle. Methods. Rabbits were anesthetized, intubated, and mechanically ventilated with O-2 (FiO(2) = 0.50). Animals were then given 5 mg/kg gentamicin either intravenously, intramuscularly (IM), or intratracheally (IT) gentamicin Pu lmoSpheres((R)) formulation, instilled in 1.8 ml/kg of liquid perflubron ve hicle. Serum and lung lobe sections were collected at multiple time points and assayed for gentamicin content. Results. Serum gentamicin levels peaked at 64.7 mug/ml, 11.2 mug/ml, and 5. 0 mug/ml following intravenous, IM, and IT administration, respectively. Ab solute bioavailability at 8 h for IM administration was 76.8% and 57.0% whe n delivered IT. Although peak lung levels of drug were reached within I h, total lung gentamicin concentration after IT administration was more than t wo orders of magnitude greater than that achieved following IM administrati on (680,540 vs. 4,985 mug min, respectively) with significant levels of the antibiotic remaining in the lung even after 1 week. Conclusions. High levels of gentamicin in lung tissue can be achieved by in stillation of a gentamicin PulmoSpheres((R)) formulation in a perflubron ve hicle, termed liquid dose installation, without reaching toxic systemic lev els allowing for increased local delivery of agents such as gentamicin at t he site of the infection.