Enzymatic and nonenzymatic biotransformation of drugs administered to the airways represents an emerging and important area of research. Most is known about of the degradation of select bronchoactive peptides in the airways and a discussion of the findings relating to substance P serves as an example of the nature, efficiency, and regional differences in pulmonary metabolism. Substance P perfused through the pulmonary vasculature is subject to enzymatic metabolism by angiotensin-converting enzyme (presumably associated with vascular endothelium) and neutral endopeptidase . When delivered to the airway lumen, it is principally degraded by neutral endopeptidase and other (as yet to be identified) peptidases [136,137], a result that is consistent with the observed presence of neutral endopeptidase on airway epithelial cells . Enzymatic biotransformation regulates the bronchoconstrictor activity of the tachykinins to the extent that aerosolized substance P, which normally lacks bronchomotor activity, induces significant bronchoconstriction after animal pretreatment with a neutral endopeptidase inhibitor . The expression of neutral endopeptidase has been shown to be influenced by several factors. For example, viral infection, cigarette smoke, and lung tumorigenesis inhibits the expression of neutral endopeptidase [139-141], whereas glucocorticoid treatment increases neutral endopeptidase expression in epithelial cells . Therefore, diseases and therapeutic interventions have the potential to influence the metabolic fate of an inhaled substance.
Metabolic processes in the lung may be exploited in drug design, as is the case for bitolterol. This compound is administered as an inactive ester that must be hydrolyzed by tissue-associated esterases to form the active b2-adrenoceptor agonist colterol . This process takes several hours and results in a long duration of action of the bronchodilator.
From the foregoing, it is evident that the activity of inhaled drugs can be influenced by metabolic processes in the airways and that various interventions can influence drug activity by modifying metabolic processes. Cellular location of enzymes would be anticipated to have important consequences on the activity of aerosols. For example, enzymes associated with pulmonary endothelium will have little influence on the actions of drugs designed to exert pharmacological activity in the central airways but will be important in regulating the actions of aerosolized therapeutic agents destined for systemic administration via the pulmonary circulation. These considerations notwithstanding, further research into drug biotransformation in the airways is necessary, particularly in the central airways, where aerosol therapy is commonly targeted.
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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.