Airway liquid: a barrier to drug diffusion?

Correspondence: J.G. Widdicombe, Sherrington School of Physiology, St Thomas' Hospital Campus (UMDS), Lambeth Palace Road, London SE1 7EH, UK. The paper by HOHLFELD et al. [1] in this issue shows that, in rats, bronchoconstriction due to inhaled acetylcholine is inhibited by inhaled aerosols of surfactant. Bronchoconstriction was assessed from changes in total lung resistance; other parameters of airway calibre were not affected. The authors conclude that this inhibition is due to the surfactant setting up a hydrophobic barrier on the surface of the airway liquid that is relatively impermeable to hydrophilic substances such as acetylcholine. The results are important. Not only do they point to possible therapeutic approaches, for example to prevent allergen entry in asthma and even allergic rhinitis, but they also add to our understanding of the way in which inhaled drugs enter the airway mucosa. Before any inhaled substance can enter the tissues, it must first dissolve in the airway surface liquid (ASL) [2, 3]. This applies to drugs used to treat diseases such as asthma, to agents used to test bronchial responsiveness, to toxic agents such as pollutants, and even to "soluble" particles such as liposomes. The volume and chemical nature of the ASL is crucial in three respects: 1) If the inhaled agent binds to the mucins in the ASL then it may be removed by mucociliary clearance and thus be rendered relatively ineffective. The degree of binding would depend on the quantities of agents and mucins, and on their mutual binding affinities (tightness of binding) and capacities (quantity that can be bound) [4]. Once bound, the agent would be rendered unavailable until it is slowly released, perhaps higher up the respiratory tract. We know almost nothing about the binding properties of airway mucins to the agents used to test and treat disease, and this process is usually ignored or assumed to be insignificant. Airway mucins bind some antibiotics and also diethylenetriamine pentaacetic acid (DTPA) [4], the last with high affinity but small capacity [5]. Since mucins are negatively charged, binding would be greater for positively charged chemicals. If binding occurs it will reduce and delay the effectiveness of a drug. 2) The ASL will constitute a diffusion barrier for inhaled agents. The strength of the barrier will depend on its thickness and physical and chemical nature, and on the properties of the diffusing agent. For example, if the barrier has a hydrophobic layer (see below), penetration by a hydrophilic chemical will be hampered. Most drugs used in treatment and testing of airways' diseases are hydrophilic. However, steroids, for example, are lipophilic. There have been few measurements of diffusion through layers of respiratory mucus [5], but several with gastro-intestinal mucus [4, 6–8]. These indicate that, if the ASL layer is thin, the diffusion barrier should cause only an insignificant delay to drug entry into the airway mucosa. Note that the diffusion barrier will slow down entry of an agent into the tissues but, unlike binding, will not reduce it. To take an example, if the ASL thickness is 50 μm (see below), and its properties as a diffusion barrier are similar to those of intestinal mucus, the permeability coefficient for the lipophilic agent antipyrine would be about -9×10-4 cm·s-1 and for the hydrophilic agent phenylalanine about -8×10-4 cm·s-1 [6]. Permeability coefficients through saline buffer are approximately 2–2.5 times larger (table 1). Thus the diffusion barrier through ASL compared with saline could be appreciable. Similar figures for gastro-intestinal mucus have been reported [7, 8]. If the ASL was thinner than 50 μm, the permeability coefficient would be proportionally greater. These values should be compared with those for the tracheal epithelium, which are given in table 1 [6, 9–11]. Although these figures may not be strictly comparable, due to differences in methodology and agents, they do suggest that for a lipophilic agent a 50 μm layer of mucus is 3–40 times less of a barrier than the epithelium, and for a hydrophilic agent the difference is 3,600–5,000 fold. Unlike a mucus sheet, the epithelium is far more permeable to lipophilic than to hydrophilic compounds. Damage to the epithelium, as may occur in asthma [12], greatly increases the permeability to hydrophilic, but not to lipophilic agents. 3) The volume, and therefore the thickness, of the ASL will determine the rate of entry of a drug into the tissues [2, 3]. For any given quantity (Q) of an aerosolized drug, its concentration (C) will vary with ASL volume (V) and, since the airway surface area (S) is fairly EDITORIAL