Lung Dosimetry: Pulmonary Clearance of Inhaled Particles

In lung dosimetry of inhaled particulate compounds one has to consider both deposition and clearance kinetics throughout the respiratory tract. The deposition is governed essentially by particle size, ventilatory parameters, as well as airway characteristics, whereas the clearance of particulate compounds, once deposited, is dependent on physicochemical characteristics of the compound. Predictive models of particle deposition for specific regions in the lung or specific airway generations can be applied to estimate regional and local doses of an inhaled compound. The main clearance mechanism for insoluble particles deposited in the conducting airways is via the mucociliary escalator. Soluble particles are cleared mainly by diffusional and pinocytotic processes from this region, depending on their lipo- or hydrophilicity. The main clearance mechanism for insoluble particles in the alveolar region is based on the function of the alveolar macrophages that effectively phagocytize deposited particles and transport them toward the mucociliary escalator. Soluble compounds deposited in the alveolar region will mainly be cleared by diffusional and pinocytotic processes via inter- or transcellular pathways where lipophilicity, hydrophilicity, and molecular size play an important role. Knowledge of the retention characteristics of specific inhaled compounds is important for developing strategies for targeting regions of the respiratory tract. In addition to applications in diagnostic and therapeutic aerosol delivery, knowledge of lung dosimetry is also important for extrapolation of results from animal studies to humans, in particular when applied to toxicological investigations. Using inhaled particles as carriers for other chemical compounds or modulating uptake mechanisms should also be considered as a means for increasing the pulmonary retention of otherwise rapidly cleared compounds. Lung clearance and retention processes of inhaled particulate compounds may be significantly altered in the diseased lung, thereby changing the clearance kinetics of soluble and insoluble particulate compounds, which has to be considered in pharmaceutical applications.