The present work was aimed to compare levofloxacin pulmonary disposition after systemic or inhalatory delivery and to evaluate the influence of respiratory pattern on lung distribution. An experimental model of the isolated lung of the rat was used. Twenty-four Wistar rats were distributed in four groups receiving levofloxacin under different experimental conditions including systemic or pulmonary delivery and higher or lower respiratory frequency with lower or higher tidal volume, respectively. Levofloxacin (500 microg) was administered as a bolus injection or by inhalation. Lung tissue samples as well as efferent and broncoalveolar fluid were collected. Quantification of levofloxacin levels in all samples was performed by a high-performance liquid chromatography (HPLC) technique. Pulmonary distribution coefficient of levofloxacin after systemic delivery showed mean values of 1.19+/-0.13 and 3.34+/-0.61 ml/g for each respiratory pattern assayed. The partition coefficients estimated from simultaneous drug level in lung tissue and efferent fluid (EF) are in agreement with the above values. Comparison of systemic and pulmonary administration reveals statistical significant differences between partition coefficients showing much higher values for the latter route (8.01+/-5.53 versus 2.86+/-1.35). In conclusion, inhalation compared to systemic administration improves levofloxacin access to the lung tissue; the experimental approach used here to assess the pulmonary drug disposition may be a useful model for biopharmaceutical studies of inhaled therapeutics.