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This study was designed to clarify the intrapulmonary pharmacokinetics and distribution characteristics of drugs in order to develop better therapies for respiratory diseases, including respiratory infections and pulmonary fibrosis. The distribution characteristics of three macrolide antimicrobial agents-clarithromycin, azithromycin, and telithromycin-in plasma, lung epithelial lining fluid (ELF), and alveolar macrophages (AMs), were examined for the optimization of antimicrobial therapy. The time course of the uptake of these agents in ELF and AMs, following oral administration to rats, resulted in markedly higher concentrations than that in plasma. The high concentration of the agents in AMs was due to their sustained distribution to ELF via multidrug resistance protein 1 and to high uptake by AMs themselves via active transport mechanisms and trapping and/or binding in acidic organelles. The intrapulmonary pharmacokinetics of aerosolized model compounds administered to animals with bleomycin-induced pulmonary fibrosis via aerosol formulations of model compounds (MicroSprayer) were then evaluated. The concentrations of these compounds in the plasma of pulmonary fibrotic rats were markedly higher than in that of control rats. The expression of epithelial tight junctions decreased in pulmonary fibrotic lesions. The accumulation of extracellular matrix inhibited the intrapulmonary distribution of aerosolized model compounds, indicating that aerosolized drugs are easily absorbed after leakage through damaged alveolar epithelia, but cannot become widely distributed in the lungs because of interruption by the extracellular matrix. This review provides useful findings for the development of therapies for respiratory infections and pulmonary fibrosis.

Intrapulmonary Pharmacokinetics and Drug Distribution Characteristics for the Treatment of Respiratory Diseases