General Considerations

Some years ago, most drugs that were targeted to the respiratory tract were used for their local action, that is, nasal decongestion, bronchodilation, and so on. In recent years, it has become apparent that the lining of the upper respiratory tract (i.e., the nasal mucosa) and the airways may also be used for the absorption of a drug for its systemic effect, particularly if this route of administration avoids the metabolic destruction observed with alternative routes of administration [1,2]. This area has attracted considerable interest, particularly with regard to the delivery of peptides and proteins, which suffer from rapid degradation by peptidases by the oral route. Numerous studies have recently demonstrated that drugs can be administered systemically by application to the respiratory tract, either to the nasal mucosa or to the lungs.

The lung provides substantially greater bioavailability for macromolecules than any other port of entry to the body [3,4]. Large proteins (18-20 kDa), such as human growth hormone, show pulmonary bioavailability approaching or exceeding 50% [5], while bioavailability might approach 100% for small peptides and insulin (< 6 kDa) placed in the lung compared to delivery by subcutaneous injection. The lung has several dynamic barriers, the first of which is the lung surfactant layer, which is probably a single molecule thick. Spreading at the air/water interface both in airway and alveolar surface, this surfactant layer may cause large molecules to aggregate, which might enhance engulfment and digestion by air space macophages. Interaction of some drug molecules administered by inhalation may interfere with surfactant function and lead to an increase in local surface tension, which could produce either collapse of the alveoli or edema through altered transpulmonary pressures [6]. Below the molecular layer(s) of lung surfactant lie the epithelial surface fluids. Macromolecules must defuse to get to the epithelial cell layer. It has been shown that the volume and composition of the surface liquids in this layer are regulated by ion transport in pulmonary epithelium [7]. Patton [8] mentioned in his review that in the airway, the thickness of the surface fluid is thought to average about 5-10 mm, gradually decreasing distally until the vast expanse of the alveolar is reached, covered with a very thin layer of fluid that averages about 0.05-0.08 mm thick. This layer may be several microns thick in pooled areas and as thin as 15-20 nm in other areas. The lining fluid of the airway contains various types and amounts of mucus, except on the alveoli, which concentrate on top of the surface. This mucus blanket, which covers the conducting airways and which is moved by ciliated cells in an upward direction to the pharynx, may affect pulmonary drug delivery. Drug transport may be affected as a result of drug binding to mucus compounds; increases in the thickness of the mucus layer may reduce the rate of drug absorption, and a change in the diameter of the airways may also affect the sites of drug deposition.

The ultrastructure of the respiratory membrane is unique by virtue of its function. A diagrammatic representation of the respiratory membrane is shown in Figure 1. The respiratory membrane basically comprises two main layers. The first layer is the alveolar epithelium, which consists of at least three different cell types: alveolar types I, II, and III or brush cells and migratory alveolar macrophages.

Figure 1 Diagrammatic representation of the ultrastructure of the respiratory membrane. Arrows indicate the passage of drugs (horizontal heavy lines) through the respiratory membrane after alveolar or capillary exposure, or of metabolites (horizontal broken lines) generated in the epithelial or endothelial layers. Key: (1) monomolecular surfactant layers, (2) thin fluid film, (3) interstitial space, (4) endothelial capillary basement membrane, (5) drug transport from the alveoli, (6) absorption of drug into endothelial cells from the circulation, (7) transport of drug from the circulation to alveolar epithelium, (8) transport of drug from the circulation to the alveoli. (From Ref. 102. Reproduced by permission, CRC Press, Inc.)

Figure 1 Diagrammatic representation of the ultrastructure of the respiratory membrane. Arrows indicate the passage of drugs (horizontal heavy lines) through the respiratory membrane after alveolar or capillary exposure, or of metabolites (horizontal broken lines) generated in the epithelial or endothelial layers. Key: (1) monomolecular surfactant layers, (2) thin fluid film, (3) interstitial space, (4) endothelial capillary basement membrane, (5) drug transport from the alveoli, (6) absorption of drug into endothelial cells from the circulation, (7) transport of drug from the circulation to alveolar epithelium, (8) transport of drug from the circulation to the alveoli. (From Ref. 102. Reproduced by permission, CRC Press, Inc.)

The epithelial layer has a thin fluid film that is covered by a monomolecular layer of surfactant. Unlike the endothelium, the epithelial basement membrane is not distinct but is usually observed to be fused into one layer with the epithelial cells. The second layer, the capillary endothelium, with its basement membrane, is separated from the endothelial layer by an interstitial space. The overall thickness of these layers is less than 0.1 mm and in some areas of the respiratory tract is as thin as 0.1 mm. Exposure of the respiratory tract to drugs or xenobiotics can occur by either the airways or the vasculature. Because the venous drainage from the entire body perfuses through the alveolar capillary unit, drugs that are administered at sites other than by direct application to the respiratory tract may still find their way into lung tissue, either by unique lung uptake (endothelial) mechanisms or by designed targeting. In this case of drug delivery by inhalation administration, several factors can affect drug absorption and clearance from the respiratory tract.

The absorption of drug molecules through lung epithelium has received more attention in recent years. The lung is lined by a layer of epithelial cells that extends from the ciliated columnar cells of the conducting airways by an abrupt transition to the flattened cells of the alveolar region. Earlier studies by Schanker et al. [9,10] showed that most xenobiotics are absorbed by passive diffusion at rates that correlate with their apparent partition coefficients at pH. 7.4. Thus, like the gastrointestinal membrane, the endothelial membrane appears to behave like a typical phospholipid membrane. However, poorly lipid-soluble compounds generally diffuse more rapidly than would be expected, suggesting that pulmonary epithelial diffusion may occur through aqueous pores. In addition, certain drugs (e.g., disodium cromoglycate) are known to undergo carrier-mediated transport, which is unique for lung epithelial cells. Pulmonary microvascular endothelial cells form a restrictive barrier to macromolecular flux, even more so than arterial cells. The mechanisms responsible for this intrinsic feature are unknown. However, cAMP improves endothelial barrier function by promoting cell-cell and cell-matrix association [11,12]. Endothelial cells form a semipermeable barrier to fluid and protein transudation in the noninflamed lung that limits accumulation in interstitial spaces [13]. Inflammatory mediators increase pulmonary macrovascular permeability [14,15].

Recently, significant emphasis has been placed on elucidating the cellular and molecular mechanisms governing the pulmonary microvascular endothelial cell response to inflammatory stimuli [16]. Constituent protein flux is greatly attenuated in response to inflammation [17,18]. This enhancement in barrier property is associated with increased expression of focal adhesion complexes that promote cell-cell contact [19-21]. Increases in cAMP may account for enhanced barrier properties of pulmonary endothelial cells, since elevating cAMP may reduce inflammation permeability by promoting cell-cell contact. When an aerosolized drug is administered to the respiratory tract, it must cross the epithelial cell barrier to enter either the lung tissue (topical effect) or the circulation (systemic effect). The pulmonary epithelium has a high resistance to the movement of water and lipid-insoluble compounds, which usually diffuse through the tissue very slowly, either by a vesicular mechanism or by leaks in the intercellular tight junctions. The characteristic feature of this type of junction bestows on the epithelium a 10-fold greater resistance to the permeation by hydrophilic probe molecules than that of the pulmonary vascular endothelium. For the delivery of macromolecules, such as peptides and oligonucleotides, an understanding of these mechanisms of epithelial transport is crucial.

Enhancement of drug uptake by altered junctional (paracellular) or vesicular (transcellular) transport (Fig. 2) is an active area of research [22,23]. The paracellular transport mechanism provides an explanation for the pulmonary absorption of peptides and proteins # 40 kDa.

The pore radius of paracellular channels between epithelial cells is about 1 nm, which is a quarter of the pore radius found between the adjacent endothelial cells. Thus, macromolecules which molecular radii greater than 2 nm are completely excluded from paracellular transport (e.g., horseradish peroxidase, MW 40,000; molecular radius > 3 nm). This implies that the main mechanism of transport of large particles across normal pulmonary epithelium is either by endocytosis by the epithelium itself or by phagocytosis and subsequent penetration of the epithelium. Of note, the epithelial tight junction is characterized by a network of sealing strands made up of a row of protein molecules on each adjacent cell wall; these molecules interlock like a zipper. The greater the number of strands, the more impermeable is the junction. However, it is hypothesized that the intercellular strands can reversibly "unzip" to permit lymphocytes, phagocytic macrophages, and polymorphonuclear leukocytes to enter or leave the airspace. Tight junction structure and function is now a very

Figure 2 Transcellular and paracellular transport pathways across lung epithelial cells.

active area of research. They used to be thought of as simple cell adhesions composed of lipid structures [24]; however, it is now known that these junctions consist of a complex structure of multiple proteins that serves as a dynamic mechanism for the fastening of cells to each other. In fact, there are around 60 miles of cell junction in human airways and over 2000 miles in the alveolar region. The pulmonary endothelial cell barrier is relatively permeable to macromolecules as compared to the epithelium.

Vesicular transport (endocytosis) of drugs may well depend on molecular structure and size. In this respect, the ionic structure of the pulmonary membrane may be an important factor to consider. The predominance of negative charge in the basement membrane structure and the interstitia of the lung [25] will no doubt influence the rate of transport of charged molecules by dipolar interactions. It has been observed that pulmonary absorption of similarly macromolecular fluorophore-labeled poly(hydroxyethylaspartamide) derivatives, either neutral or positively or negatively charged, occurs via both carrier-mediated and diffusive mechanisms. The highest rate of absorption was observed with the polyanionic derivative [26]. A study has also shown that pulmonary absorption of some peptidase-resistant polypeptides [poly-(2-hydroxyethy I)-aspartamides] administered intratracheally to the airways in isolated rat lung is molecular weight dependent [27]. Approximately 70% absorption of a 0.2-mg dose of a 3.98-kDa polymer occurred in 100 minutes, whereas for larger polymers the absorption rates appeared to be slower and suggested a molecular weight cutoff point between 4 and 7 kDa. Nevertheless, according to the investigators, the results strongly suggest that systemic protein and peptide delivery by aerosol is feasible because even the largest polymers (11.65 kDa) were absorbed at finite rates. Intratracheally administered cytochalasin D and calcium ions are known to alter junctional transport by disruption of parts of the cytoskeleton that are attached to tight junctions. Airway epithelium appears to actively secrete chloride ions coupled with sodium ion; the exact organization of these ion pumps remains to be established, but they appear to be dependent on intracellular levels of cyclic adenosine monophosphate (cAMP). In this respect, target receptors on epithelial cell membrane surfaces may be exploitable in the development of bioadhesive carriers conjugated to a drug molecule, resulting in selective binding and rapid internalization. In addition, the observed specific uptake of certain drugs into pulmonary tissue is an intriguing area of study, particularly as it relates to the development of lung-targeting strategies. Both of these approaches to pulmonary targeting of drugs are discussed in later sections of this chapter.

A final, and not insignificant, consideration is the problem of drug metabolism in the respiratory tract. Although a large body of data indicates that pulmonary metabolism is generally relatively lower than hepatic metabolism [28], it is clear that nearly all of the drug metabolism activities found in the liver are present in the respiratory tract [1,25]. In addition, some respiratory tissues contain enzyme activities much higher than corresponding activities found in the liver [29]. Metabolism of drugs in respiratory tract tissue will most likely lead to the formation of more than one metabolite because of the variety of enzymes and their differential location throughout the respiratory tract. The metabolic profile of a particular drug will depend on a number of factors, which include ease of access of the drug to the enzyme active site, availability of cofactors, Vmax and Km of the enzyme(s), and possible competition at the active site with other exogenous or possible endogenous substrates and inhibitors, inducers, activators, and so on. Other factors are cell type, age, and health. A recent review addressed the localization of drug-metabolizing enzymes in the respiratory tract [1]. Although pulmonary metabolism may be seen as a disadvantage, particularly in the case of peptides and proteins, because of the wide variety of peptidases and proteinases found in respiratory tract tissues, pulmonary activation of drugs by site-specific metabolism of a prodrug form is a possible way to increase selectivity and duration of action. For example, the bronchodilator bitolterol is converted into its active metabolite by hydrolysis in the respiratory tract (see the section on prodrug approaches), and the antitumor drug hexamethylmelamine owes its activity to pulmonary activation by N-demethylation [30].

Because the main goal of drug delivery is to direct the drug to the target receptors while minimizing interactions with other possible sites of action, the question of receptor specificity is of primary importance in drug design. Although other factors that may affect receptor targeting, such as rate of delivery regional distribution and pharmacodynamics, are of significance, this chapter focuses on structure-activity considerations associated with receptor targeting in the lung.

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