Biomedical Engineering Reference
In-Depth Information
macromolecular absorption generally appears to be inversely related to molecular mass, up to a
mass of about 500 kDa. Many peptides/proteins delivered to the deep lung are detected in the
blood within minutes, and bioavailabilities approaching/exceeding 50 per cent (relative to s.c.
injection) have been reported for therapeutic proteins such as colony-stimulating factors and
some interferons. Although not completely understood, such high pulmonary bioavailability may
stem from:
•
the lung's very large surface area;
•
their low surface fl uid volume;
•
thin diffusional layer;
•
relatively slow cell surface clearance;
•
the presence of proteolytic inhibitors.
Additional advantages associated with the pulmonary route include:
•
the avoidance of fi rst-pass metabolism;
•
the availability of reliable, metered nebulizer-based delivery systems capable of accurate dosage
delivery, either in powder or liquid form;
•
levels of absorption achieved without the need to include penetration enhancers which are gen-
erally too irritating for long-term use.
Although obviously occurring in practice, macromolecules absorbed via the pulmonary route
must cross a number of biological barriers to get into the blood. These are:
•
a protective monolayer of insoluble phospholipid, termed 'lung surfactant', and its underlying
surface lining fl uid, which lies immediately above the lung epithelial cells;
•
the epithelial cells lining the lung;
•
the interstitium (an extracellular space), and the basement membrane, composed of a layer of
interstitial fi brous material;
•
the vascular endothelium, i.e. the monolayer of cells that constitute the walls of the blood vessels.
Passage through the epithelium and endothelial cellular barriers likely represents the great-
est challenge to absorption. Although the molecular details remain unclear, this absorption
process appears to occur via one of two possible means: transcytosis or paracellular transport
(Figure 4.6).
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