Pulmonary epithelium permeability

Relative to the gastrointestinal mucosa the pulmonary epithelium possesses a high permeability to water soluble molecules, which is an advantage with dmgs such as sodium cromoglicate (IX), a bischromone with two carboxylic acid groups and a pK of approximately 1.9. The dmg is well absorbed from the... 

The vascular endothelium, which is the final barrier to systemic absorption, is more permeable to macromolecules than is the pulmonary epithelium. 

Keywords Bronchial epithelium Pulmonary drug absorption Pulmonary metabolism Drug transport Permeability... 

It should be noted that the permeability per surface unit of alveolar epithelium per se is not particularly high. The significant absorption found for various substances after pulmonary administration is rather explained by a number of beneficial factors such as the large surface area of the alveoli, the low volume of the epithelial lining fluid, the relatively thin diffusion layer, the absence of mucociliary clearance from the alveoli as well as the limited enzymatic activity in the lining fluids. 

In general, when the cells of the endothelium in the lungs are the target cells of interest (see Chapters 7 and 9 on aspects of targeting drugs to endothelium in inflammatory diseases and cancer, respectively), systemic administration seems the route of choice. Bronchial epithelium on the other hand can more easily be reached via the pulmonary route. The accessibility of other cells in the lungs is most hkely governed by disease conditions, factors that can affect epithehal permeability and vascular permeability, and others as described earher. 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

Van Zyl et al. reported on the diffusion of ipratropium through porcine bronchial epithelium tissue [74], In principle, ipratropium is administered via the respiratory tract by inhalation to treat pulmonary diseases associated with bronchoconstriction. Therefore, pulmonary absorption by bronchial tissue determines its local efficacy and was thus investigated in a diffusion cell in vitro. Bronchial epithelium was equilibrated in PBS and discs of 4 mm2 were mounted on that diffusion cell separating the donor and receiver compartment. The donor compartment contained the drug dissolved in PBS (1 mg/ml) and the receiving chamber was permanently flushed with a low flow (1.5 ml/h) of PBS thus allowing time-resolved fractionation for subsequent direct analysis by LC-ESI MS/MS in MRM mode. Transition to the product ion at m z 124 was monitored for quantification (Table 9). The transfer of ipratropium was characterized by the flux (about 220 ng/cm2/min) and the permeability coefficient calculated to be 1.6 x 10-8 cm/s. 

Capsaicin, like the other irritant RCAs, also causes bronchoconstriction, but the mechanism is uncertain. Capsaicin releases substance P that can cause bronchoconstriction directly by activation of specific receptors or by release of histamine or other mediators. It may also cause reflex bronchoconstriction by stimulating C fibers in both pulmonary and bronchial circulation. Therefore, bronchoconstriction may be secondary to substance P release, or to a vagal reflex. The altered neurophysiology of sensory neurons in the airway mucosa induces the release of tachykinins and neurokinin A, which causes neuro-mediated inflammation of the epithelium, airway, blood vessels, glands, and smooth muscles. This leads to bronchoconstriction, mucus secretion, enhanced vascular permeability, and neutrophil chemotaxis. 

The biological actions of capsaicin are primarily attributable to release of the neuropeptide substance P, calcitonin gene-related peptide (CGRP), and neurokinin A from sensory neurons. These transmitters from primary sensory neurons communicate witir other cell types. They produce alterations in the airway mucosa and neurogenic inflammation of the respiratory epithelium, airway blood vessels, glands, and smooth muscle. Alterations in multiple effector organs lead to bronchoconstriction, increased vascular permeability, edema of the tracheobronchial mucosa, elevated mucosal secretion, and neutrophil chemotaxis (Tominack and Spyker, 1987). Capsaicin-induced effects of bronchoconstriction, vasodilation, and plasma protein extravasation are mediated by substance P. In addition, substance P can cause bronchoconstriction through stimulation of c-fibers in pulmonary and bronchial circulation. 

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