Mechanism of Drug Clearance and Pharmacokinetics of Disposition

The first purified and characterized drug substances were administered as aerosols as a topical treatment for asthma approximately 50 years ago. More recently, drugs have been evaluated for systemic delivery by this route. For each category of drug, the mechanism of clearance from the airways must be considered. These mechanisms may be listed as mucociliary transport, absorption, and cell-mediated translocation. The composition and residence time of the particle will influence the mechanism of clearance.

The importance of clearance mechanisms from the lungs relates to the action of the drug. For drugs that act in the lungs, such as bronchodilators or anti-inflammatory agents, an extended residence time in the lungs might be beneficial. For drugs intended to act systemically, such as ergotamine alkaloids for migraine or insulin for the treatment of diabetes mellitus, rapid absorption may be desirable. This is not to imply that all systemically acting agents must be delivered rapidly, but this allows a contrast in rates of delivery.

The nature of the mechanisms involved and the interaction with the aerosol particles complicate the pharmacokinetics of drug clearance from the lungs. Figure 3 illustrates the sites of deposition in the lungs and the nasal, oropharyngeal, tracheobronchial, and pulmonary regions. Also shown in this figure are the routes for clearance by absorption into the blood circulation, by mucociliary transport to the gastrointestinal tract, and cellmediated transport to the lymphatics and from there to the blood circulation.

Mucociliary transport in the conducting airways takes approximately 24 hours from the lung periphery to the epiglottis. Absorption takes place at a rate dictated by the physicochemical properties of the drug (hydrophobic, hydrophilic, strong or weak electrolyte, molecular weight). These properties impact on the paracellular and transcellular mechanisms of transport across the alveolar or bronchiolar epithelium. Studies of fluorescent dextrans of a range of molecular weights have shown that paracellular transport occurs more rapidly for small-molecular-weight molecules than for

Figure 3 Sites of deposition in the lungs, oropharynx, and tracheobronchial and pulmonary regions.

large molecular weight ones (22). A plot of log clearance (min-1) against log molecular weight (D) appears to be linear in the range of clearances of 10~1 —10~4 for molecular weights of 102—105 Da, respectively (22). The data were collected for a number of different species (rat, rabbit, dog, sheep, lamb, dog, and human).

Particles that exhibit long residence times in the periphery of the lungs, beyond the mucociliary escalator, are subject to uptake by alveolar macrophages, phagocytic cells responsible for clearing debris from the pulmonary region of the lungs. These cells are also the primary immunological defense, presenting the initial response to antigenic materials, usually foreign material of biological origin including infectious microorganisms (bacteria, viruses, and fungi). Cellular clearance may take weeks or months depending on the nature of the particles.

Mathematical models for drug disposition have been proposed (23) and elaborated upon (24). The latter model proposed dividing the airways into tracheobronchial and two pulmonary regions, long and short residence time regions, also considering the availability of drug that enters the gastrointestinal tract. A series of equations were derived for the fraction remaining in each of the regions under steady-state conditions. These models examine thoroughly the influence of the physicochemical properties on drug disposition from the lungs. More subtle models have also been evaluated on the basis of receptor occupancy of glucocorticoids (25).

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