Pore pathway

Camenisch, G. Folkers, G. van de Waterbeemd, H., Shapes of membrane permeability-lipophilicity curves Extension of theoretical models with an aqueous pore pathway, Eur. J. Pharm. Sci. 6, 321-329 (1998). 

There are two routes potentially involved in drug absorption across the nasal epithelial barrier the transcellular and paracellular routes [20], Several experimental evidences dealing with the mechanism of transnasal permeation support the existence of both lipoidal pathyway (i.e., transcellular route) and an aqueous pore pathway (i.e., paracellular route). 

Other workers [7] propose that an aqueous pore pathway forms at sites of corneodesmo-some degradation (lacunar domains) embedded within the lipid bilayers. They suggest that under high stress conditions (such as extensive hydration, iontophoresis, or ultrasound) the scattered, discontinuous lacunae expand, interconnect, and develop a continuous pore pathway. Drugs would diffuse easily down this route. 

Menon, G.K., and P.M. Elias. 1997. Morphological basis for a pore-pathway in mammalian stratum comeum. Skin Pharmacol 10 235. 

An example for the pore pathway is discussed using the example of sulfonamides. For this class of compounds it is generally accepted that the degree of ionization determines the antibacterial activity, the ionized form being more potent then the neutral form. Total ionization, however, leads to decreased activity in whole cells because cell wall permeation becomes the rate-limiting step [99-101]. The possible effect of molecular size on cell wall permeation has been studied on a series of substituted 5-sulfanilamido-l-phenylpyrazoles that show only a small variation in pKa values but a large difference in molecular weight [102]. 

The speed of response of a humidity element will depend on the rate of diffusion of the ambient atmosphere into the pores of the sensing element. The element must therefore be thin in section and may contain a system of larger pores to reduce the length of the finer pore pathways into which gas must penetrate. Electrodes covering major surfaces must be porous. 

However, these general observations do not take into account the cyclical changes in the vaginal epithelium, which exert profound effects on vaginal absorption, especially for hydrophilic compounds. The permeability coefficient for the vaginal membrane (Pm) is equal to the sum of the permeability coefficient through the lipid pathway (P ) and the pore pathway (Pp) ... 

Fig. 5), the vaginal uptake of both alkanols and alka-noic acids also follows a first-order rate process and is dependent on the drug concentration in the vaginal fluid. The results agree well with a physical model that has a hydrodynamic diffusion layer in series with the mucosal membrane, that consists of two parallel pathways a lipoidal pathway and an aqueous pore pathway (Fig. 6). Immediately behind the mucosa (serosal side) a perfect sink is maintained by hemoperfusion. 

The stratum corneum is the outermost layer of the epidermis and has a thickness of 10-15 pm. It is the principal barrier for the transport of most solutes (except for very lipophilic compounds) across the skin. The stratum corneum is a continuous heterogeneous structure that consists of approximately 10-25 layers of closely packed dead keratinized cells (corneocytes) cemented together by intercellular lipids. The intercellular lipids in the stratum corneum are in the form of multiple lamellar bilayers composed mainly of ceramides, cholesterol, and fatty acids. Proteins in the stratum corneum are largely concentrated within the corneocytes as keratin fibrils. The transport of lipophilic compounds across the stratum corneum is related to the intercellular lipids (lipoidal or intercellular pathways). On the other hand, it is believed that the transport of polar and ionic compounds is related to pathways with aqueous properties (the polar or pore pathways) when the stratum corneum is under a hydrated state. ... 

To further illustrate the mechanisms of chemically and physically enhanced transdermal transport, a transdermal transport model will be discussed here. Generally, the permeability of the stratum corneum can be divided into parallel lipoidal and pore pathway... 

A more general equation for the transport of polar and ionic permeants across the pore pathway in the membrane is ... 

Surgical thinning of the sclera predictably increases its permeability however, neither cryotherapy nor transscleral diode laser application alters permeability (4). It also increases with increasing tissue hydration (28). Scleral permeability of small molecules increases rapidly with increasing temperature (23). This low activation energy supports the existence of an aqueous pore pathway rather than a transcellular one. This paracellular pathway presumably traverses the aqueous media of the mucopolysaccharide matrix. 

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