In the alveolus, aerosolized drug is deposited in a layer of surfactant, a lipoprotein compound that lines the alveolar surface and reduces alveolar surface tension. Drug deposited in the surfactant may diffuse laterally through the surfactant [18], decreasing focal concentrations. Absorption of compounds presented to the alveolar epithelium is determined by molecular size and lipophilicity or hydrophilicity [16]. Lipophilic drugs (i.e., drugs with a high lipid and water partition coefficient) cross cell membranes rapidly and, thereby, traverse the alveolar epithelial cells, the interstitium, and the endothelium to reach the bloodstream. This process is dependent on blood flow [18] insofar as the drug moves down its concentration gradient from the alveolus to the blood. Hydrophilic compounds are less rapidly absorbed and are thought to be dependent on passage through intracellular pores in the epithelium [10,18]. Caveolae, or vesicles, have been identified in alveolar type 1 cells [19]. Macromolecules can be taken up into caveolae at the lumenal surface of the cell and be shuttled through the cell in a vesicle. The contribution of caveolae to the proposed intracellular pores remains uncertain [11], although it has been proposed that fusion of several vesicles may form discontinuous continuous pathways through the cell [19]. Molecular size of the hydrophilic molecule is thought to be the limiting factor in diffusion, and this process applies primarily to hydrophilic molecules of low molecular weight [16]. Higher-molecular-weight hydrophilic substances deposited in the alveolus may be taken up (subject to endocytosis) and removed by pulmonary alveolar macrophages. Once in the interstitium, a drug may diffuse into lymphatic vessels (an important site of loss for large molecules) or into the bloodstream through the endothelium. In addition, binding to epithelial or interstitial cellular constituents may represent an additional site of loss for compounds [16].

The rate of absorption of a compound from the alveolus is approximately two times faster than that in the central airways of a variety of species [20]. This suggests that the membrane permeability of the alveolus is greater than that of the tracheobronchial region [21]. With respect to enzymatic biotransformation of drugs in passage from the airway lumen to the target cells in the central and peripheral airways, relatively little is known. Using histochemical and biochemical techniques, a variety of enzymes have been identified in the airways, and these are summarized in Table 1. It is important to recognize that the distribution of enzymes in the central airways may differ from those in the peripheral airways [22].

At least insofar as blood-borne substances are concerned, the lung serves as an important organ of metabolism. The primary focus of this activity rests in the pulmonary endothelium, i.e., the cells lining pulmonary blood vessels. Compounds known to be metabolized by the pulmonary endothelium include adenine nucleotides (e.g., AMP, ADP, ATP), bradykinin, 5-hydroxytryptamine (serotonin), norepinephrine, and prostaglandins of the E and F series [27]. In general, these processes result in the formation of biologically inactive products. However, pulmonary biotransformation may result in bioactivation, as is the case for conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme on the endothelium. Furthermore, the processes of metabolism are selective, as exemplified by the pulmonary clearance of 5-hydroxytryptamine and norepinephrine but not of histamine or epinephrine [27]. The importance of enzymatic and degradation on the activity of aerosolized drugs remains the subject of little systematic scientific investigation. Nevertheless, the demonstration that inhibition of pulmonary neutral endopeptidase (EC24.11) uncovers a bronchoconstrictor action of the undecapeptide, substance P [28], underscores the potential importance of metabolic processes in regulating the biological actions of aerosolized compounds. The situation is confounded further by pulmonary diseases wherein activated proinflammatory cells, such as macrophages, mast cells, neutrophils, or eosinophils, release proteolytic enzymes

Table 1 Enzymes Identified in Airway Tissue

Acid phosphatase Alcohol dehydrogenase Alkaline phosphatase Amine oxidase Aminopeptidase P Angiotensin-converting enzyme Aniline hydroxylase ATPase Arylsulfatase Carboxypeptidase M Cyclooxygenase Cytochrome oxidase Endothelin-converting enzyme

Epoxide hydrase Nonspecific esterase p-Galactosidase N-Acetyl p-glucosaminidase Glucose dehydrogenase Glucose 6-phosphatase Glucose 6 phosphatase dehydrogenase p-Glucuronidase Glucuronyl transferase Glutamate dehydrogenase Glutathione-s-aryl transferase Glutathione-S-epoxide transferase Glyceraldehyde 3 phosphate dehydrogenase

Source: Refs. 22-26.

Glycerol 3 phosphate dehydrogenase 3-Hydroxybutyrate dehydrogenase Insulysin (insulin degrading enzyme) Isocitrate dehydrogenase Lactate dehydrogenase Leucine aminopeptidase Lipase

Lipoxygenase Malate dehydrogenase Metallo-endopeptidase N-Methyl transferase Monoamine oxidase Mixed-function oxidase

(cytochrome P450 dependent) NADH2 diaphorase NADPH2 diaphorase Neutral endopeptidase 24.11 Nitro oxide synthase Nitro reductase 5'-Nucleotidase Peroxidase

Phosphatidic acid phosphatase Post proline cleaving enzyme Prostaglandin dehydrogenase Succinate dehydrogenase Sulfotransferase that can modify the bioavailability of inhaled macromolecules as they are being absorbed from the airways.

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