Epithelial interfaces

Drags administered orally must cross the GI tract epithelium to be absorbed and enter the systemic circulation. Similarly, drags administered by alternative routes, such as the buccal, sublingual, nasal, pulmonary and vaginal routes, must all cross the appropriate epithelial interfaces to reach the general circulation. The types of epithelial interfaces, the barriers they pose to drag absorption, and the routes and mechanisms of drag absorption across these interfaces, are described below. 

Epithelial interfaces are involved in a wide range of activities such as absorption, secretion and protection all these major functions may be exhibited at a single epithelial surface. For example, the epithelial lining of the small intestine is primarily involved in absorption of the products of digestion, but the epithelium also protects itself from potentially harmful substances by the secretion of a surface coating of mucus. 

For the purpose of completeness, the process of phagocytosis has been described briefly here. However, it should be remembered that phagocytosis is not generally relevant to the transport of drags across epithelial interfaces, as it is only carried out by the professional phagocytes of the MPS. 

For most conventional drag molecules, which tend to be small and lipophilic, absorption occurs transcellularly, via passive diffusion across the epithelial cells. In this case, where the GI tract (or other epithelial interface) is assumed to act as a simple lipophilic barrier, absorption occurs down a concentration gradient according to Fick s Law, and the rate of absorption correlates with the lipid solubility of the drag (see Section 1.3.3.2). 

Table 3.3 The use of penetration enhancers to improve the absorption of peptides and proteins across epithelial interfaces...

In common with all epithelial interfaces (see Section 1.3.2), the epithelium of the oral cavity is supported by a basement membrane, which separates the epithelium from the underlying connective tissue layer (the lamina propria) (Figure 7.1). Oral epithelium is broadly similar to stratified squamous epithelia found elsewhere in the body, for example the skin (see Section 8.2.1), in that cells are produced by mitosis in the basal layer of the epithelium and these proliferating cells push existing cells towards the surface. The phases of this dynamic process are represented in four morphological layers ... 

The retina has two areas of direct interaction with the blood, one at the level of the retinal vessels and the other at the level of the choroid-retinal pigment epithelial interface. Thus, two structures comprise the BRB. The BRB is formed by tight junctions between the endothelial cells of the retinal vessels (the inner BRB) and by similar tight junctions in the retinal pigment epithelium (RPE, the outer BRB). 

Apical epithelial surface In the airway, surface interfacing with lumen. 

Yamashita F, Mathias NR, Kim K-J, Lee VHL (1996) Dipeptide transport properties of rabbit tracheal epithelial cell monolayers cultured at an air-liquid interface. PharmRes 15 979-983. 

Keywords Nasal absorption Air-interfaced culture Absorption enhancer Liquid-covered culture Mucociliary clearance Nasal epithelial cell mono-layer Paracellular absorption Tight junction Transcelluar absorption Drug transport... 

For AIC conditions, the apical surface of the epithelial cell layer is exposed to air after the nasal cells reached confluence on the Transwell insert, while the basolateral side is fed with culture fluid. Figure 9.3 shows TEER changes in epithelial cell layers cultured up to 20 days in LCC versus AIC methods [46], In AIC condition (initiated from day 3 after seeding), TEER peaked on day 5 and maintained above the TEER values observed for LCC counterparts. By contrast, TEER observed for LCC conditions peaked on day 2 and declined toward zero by day 15. These data indicate that human nasal epithelial cells at an air interface culture exhibit better electrophysiological characteristics than those cultured by the conventional liquid-covered conditions. 

J. J. Yang, H. Ueda, K. Kim, and V. H. Lee. Meeting future challenges in topical ocular drug delivery Development of an air-interfaced primary culture of rabbit conjunctival epithelial cells on a permeable support for drug transport studies. J Control Release 65 1-11 (2000). 

Robison TW, Dorio RJ, Kim KJ (1993) Formation of tight monolayers of guinea pig airway epithelial cells cultured in an air-interface Bioelectric properties. Biotechniques 15(3) 468—473. 

Grainger Cl, Greenwell LL, Lockley DJ, Martin GP, Forbes B (2006) Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier. Pharm Res 23(7) 1482-1490. 

Chang JE, Basu SK, Lee VHL. Air-interface condition promotes the formation of tight comeal epithelial cell layers for drug transport studies. Pharm Res 17 670-676 (2000). 

Chang-Lin JE, Kim KJ, Lee VH. Characterization of active ion transport across primary rabbit corneal epithelial cell layers (RCrECL) cultured at an air-interface. Exp Eye Res 80 827-836 (2005). 

Figure 13.3 A flowchart illustrating various steps for the preparation and maintenance of primary rabbit conjunctival epithelial cell layers, cultured under liquid-covered and air-interfaced conditions (See also color insert).

Bitterle E, Karg E, Schroeppel A, Kreyling WG, Tippe A, Ferron GA, Schmid O, Heyder J, Maier KL, Hofer T (2006) Dose-controlled exposure of A549 epithelial cells at the air-liquid interface to airborne ultrafine carbonaceous particles. Chemosphere 65 1784—1790... 

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

A deep layer rich in mucus and the origin of which is to be found in the conjunctival calyciform cells. This mucus is in relation with the apical epithelial cells via the glycocalyx. This interface between the lacrymal secretion and the epithelium influences the quality of the corneal surface. Indeed, the stability of the lacrymal secretion and the epithelial absorption of its metabolites both depend on the mucin and the apical expansions of the epithelial cells [2]. 

Used for ocular bums as soon as 1947 by Sorsby [30], the amniotic membrane is a tissue located at the interface of the placenta and the amniotic fluid. It is constituted of an unstratifled epithelium, a basement lamina, and an avascular mesenchyma. The amniotic membrane facilitates the reepithelialization by reducing the inflammatory and cicatricial reaction [31]. It helps the migration of the epithelial cells and the adhesion of the basement cells [32]. It behaves as an actual replacing basement membrane and facilitates the phenotypic... 

Of the different types of oral mucosal cell cultures that have been used [47,48], the most commonly used ones are explants of primary cultures. Small pieces of excised buccal or sublingual tissue are placed in a support system and fed with culture medium. The outgrowths obtained from these tissue explants are then transferred and grown in appropriate media. For example, outgrowths of fibroblasts [49] thus obtained have been described. Gibbs and Ponec [50] reconstructed the epithelium of mucosal tissue by placing a tissue biopsy (with the epithelial side upwards) onto a fibroblast-populated collagen gel. The explants obtained were cultured immediately at the air liquid interface until the epithelium had expanded over the gel (2-3 weeks). These explant cultures may retain many of the in vivo tissue characteristics. 

Mathias, N.R., K.J. Kim, and V.H. Lee. 1996. Targeted drug delivery to the respiratory tract solute permeability of air-interface cultured rabbit tracheal epithelial cell monolayers. /. Drug Target. 

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