Absorption and Metabolism

It is well established that the deeper in the lung the aerosol deposits, the higher is the proportion of the drug that gets absorbed into the systemic circulation. These observations span different animal species, including humans, and range from small molecules to peptides and proteins [135-140]. A number of factors contribute to this: (1) depositing the drug beyond the mucociliary escalator removes a significant mechanism competing with absorption; (2) although there is no conclusive evidence yet that different parts of the respiratory tract have different permeabilities (for a review, see Ref. 8), it would be expected that the thin alveolar membranes are more permeable than the airway surfaces; (3) the surface area grows rapidly with increasing airway generations. However, as mentioned in the earlier section on Studies with Stable Monodisperse Aerosols, the mixing of liquids on the mucosal surface appears to be incomplete, and, therefore, the rate of absorption will be probably affected by the initial surface area covered by the deposited material [55]. Even though the mechanistic aspects are not entirely understood, for systemic delivery of drugs via the lung, "deep" lung should be targeted.

For activity in the respiratory tract, the absorption should be slowed down. Controlled deposition in the tracheobronchial region to slow down the absorption is likely to be counterproductive because the overall clearance, which includes the mucociliary escalator, has to be taken in account. In other words, even if the conducting airways were less permeable to the substance in question than the lung periphery, mucociliary clearance would remove the drug more rapidly from the more central location. For locally acting drugs, selecting drug molecules with intrinsically long absorption half-life in the lung would be advantageous; pentamidine serves as an example [141]. Other drugs may require controlled-release absorption to prolong their residence time in the respiratory tract, as discussed in the previous section [37].

Studies with homogenized lung tissues show that the alveolated parts generally have higher metabolic rates than the tracheobronchial tissue [142,143]. These studies are not directly relevant, though, to the effect of a drug deposited for local activity on the respiratory lumen. On the other hand, this information is more directly pertinent to drugs intended for systemic effects. Interestingly, the bronchial circulation was shown to have a lower metabolic capacity than the pulmonary circulation [144]. There does not appear to be any clinical evidence, though, that drugs absorbed from the central airways would be metabolized to a lesser extent than following absorption from the lung periphery.

Healthy Fat Loss For A Longer Life

Healthy Fat Loss For A Longer Life

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