Aqueous pores

One of the key parameters for correlating molecular structure and chemical properties with bioavailability has been transcorneal flux or, alternatively, the corneal permeability coefficient. The epithelium has been modeled as a lipid barrier (possibly with a limited number of aqueous pores that, for this physical model, serve as the equivalent of the extracellular space in a more physiological description) and the stroma as an aqueous barrier (Fig. 11). The endothelium is very thin and porous compared with the epithelium [189] and often has been ignored in the analysis, although mathematically it can be included as part of the lipid barrier. Diffusion through bilayer membranes of various structures has been modeled for some time [202] and adapted to ophthalmic applications more recently [203,204]. For a series of molecules of similar size, it was shown that the permeability increases with octa-nol/water distribution (or partition) coefficient until a plateau is reached. Modeling of this type of data has led to the earlier statement that drugs need to be both... 

This relationship was further clarified by van de Waterbeemd in the two-step distribution model [588-590], Eater, the model was expanded by van de Waterbeemd and colleagues to include the effects of ionization of molecules, with the use of log Kd, in place of log Kp, as well as the effects of aqueous pores [49,54],... 

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). 

Cation and anion flux across cultured cell monolayers by molecular restricted diffusion within an electrostatic field of force across aqueous pores has been described with a model derived by Adson et al. (1994). The ion fluxes per cross-sectional area of the cell monolayer are defined as... 

Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane 99... 

Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane. We have learned much about ion channel function from voltage clamp and patch clamp studies on channels still imbedded in native cell membranes [1-6, 8]. A diversity of channel types was discovered in the different cells in the body, where the repertoire of functioning channels is adapted to the special roles each cell plays [5]. The principal voltage-gated ones are the Na+, K+ and Ca2+ channels, and most of these are opened by membrane depolarizations. Figure 6-5A summarizes the major functional properties of a voltage-gated... 

The nucleus is surrounded by the nuclear envelope, which takes on a lumenal structure connected to the endoplasmic reticulum. The transport of proteins into (and out of) the nucleus occurs through the nuclear pore complex (NPC), a large complex composed of more than 100 different proteins (Talcott and Moore, 1999). Because NPC forms an aqueous pore across the two membranes, small proteins less than 9 nm in diameter can pass through it simply by diffusion. However, most of the transports of both proteins and RNAs are mediated by an active transport mechanism. It is now clear that there is heavy traffic through the NPC in both directions. Proteins are not only imported into the nucleus but also actively exported from it as well. There are many reasons for nuclear export. One reason is to send some shuttle proteins back after their import another is for some viral proteins to export their replicated genomes outside the nucleus. 

Ho et al. [5] presented a theoretical model for gastrointestinal absorption of drugs (Figure 2.2), which described the biomembrane as a series of lipoidal and aqueous pores in parallel. 

It was postulated that the aqueous pores are available to all molecular species, both ionic and non-ionic, while the lipoidal pathway is accessible only to un-ionised species. In addition, Ho and co-workers introduced the concept of the aqueous boundary layer (ABL) [9, 10], The ABL is considered a stagnant water layer adjacent to the apical membrane surface that is created by incomplete mixing of luminal contents near the intestinal cell surface. The influence of drug structure on permeability in these domains will be different for example ABL permeability (Paq) is inversely related to solute size, whereas membrane permeability (Pm) is dependent on both size and charge. Using this model, the apparent permeability coefficient (Papp) through the biomembrane may therefore be expressed as a function of the resistance of the ABL and... 

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). 

Tsukita S and Furuse M [2000] Pores in the wall claudins constitute tight junction strands containing aqueous pores. J Cell Biol 149 13-16... 

Striking is the resemblance between our model structure and the multi-stranded -barrels known for various membrane proteins [42] and poreforming toxins [43]. The formation of an aqueous pore in the lipid bilayer would indeed offer an explanation for the observed bilayer conductivity induced by gramicidin S upon membrane binding [6]. The peptidedipid ratio of 1 40 at which this structure could be trapped for NMR analysis appears to be biologically relevant, as the minimum inhibitory concentration of gramicidin S corresponds to far more than an equimolar ratio of peptides per lipid molecule on the bacterial surface [34,35]. 

Compounds can cross biological membranes by two passive processes, transcellu-lar and paracellular mechanisms. For transcellular diffusion two potential mechanisms exist. The compound can distribute into the lipid core of the membrane and diffuse within the membrane to the basolateral side. Alternatively, the solute may diffuse across the apical cell membrane and enter the cytoplasm before exiting across the basolateral membrane. Because both processes involve diffusion through the lipid core of the membrane the physicochemistry of the compound is important. Paracellular absorption involves the passage of the compound through the aqueous-filled pores. Clearly in principle many compounds can be absorbed by this route but the process is invariably slower than the transcellular route (surface area of pores versus surface area of the membrane) and is very dependent on molecular size due to the finite dimensions of the aqueous pores. 

Values above 0 indicate the potential for absorption directly across the respiratory tract epithelium. Very hydrophilic substances may be retained within the mucus or for low molecular weight substances (MW < 200), could be absorbed through aqueous pores. Very low water solubility (1 mg/1 or less) and small particle size (below 1 p,m) indicates a potential for accumulation in the lung tissue. 

Water-soluble substances will readily dissolve into the gastrointestinal fluids however, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. If the molecular weigjit is low (less than 200), the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. 

Hagting A, Karlsson C, Clute P, Jackman M, Pines J (1998) MPF localization is controlled by nudear export. EMBO J 17 4127-4138 Hamman BD, Chen JC, Johnson EE, Johnson AE (1997) The aqueous pore through the translocon has a diameter of 40-60 A during cotranslational protein translocation at the ER membrane. Cell 89 535-544 Hampton RY, Rine J (1994) Regulated degradation of HMG-CoA reductase, an integral membrane protein of the endoplasmic reticulum, in yeast. J Cell Biol 125 299-312... 

Usually, PAMPA does not have any aqueous pores and is therefore not suitable for examining paracellular transport. Some cell models, for example, Caco-2 and MDCK, have a narrower tight junction than the in vivo human intestine and may underestimate paracellular transport. However, the contribution of the paracellular pathway can be added using an in silico approach [76-78]. 

There are no recent improvement in the paracellular pathway permeation models, probably because there is no specific in vitro or in vivo system to measure the paracellular pathway contribution. The paracellular pathway models was constructed using very hydrophilic compounds [107] or subtracting the contribution of transcel-lular pathway from the total passive permeation [78]. Paracellular pathway was modeled as permeation through a charged aqueous pore. A combination of size sieving function and electric field function was found to model the paracellular pathway [78, 87, 88]. 

Lipid solubility. Because cell walls comprise mainly lipid, drugs which readily dissolve in lipid will have an advantage in crossing into the cell. Conversely, water-soluble compounds may have great difficulty in crossing the lipid barrier. Aqueous pores do exist within lipid cell membranes and a proportion of the water-soluble molecules may traverse this route. 

Figure 2. Carrier (a) and channel (b) mechanisms for facilitated ion transport across the membrane. Carrier encapsulates ion and moves across the membrane and releases the ion at the other end. It shuttles in the membrane as a carrier-metal complex. Channel is, in principle, an aqueous pore structured in the membrane. Ion can traverse through the membrane more or less freely in the pore with recognition at the selectivity filter when the gate is open. Here illustrated is a voltage sensitive gate as an example. ...

Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000-30,000. See Figure 1-5A. 

In this respect the dense nonporous ion-exchange material of a membrane may be viewed as a one-phase medium. In contrast to this a porous bulk ion-exchanger (e.g., an ion-exchange bed or a single microporous ion-exchange bead) is a two-phase medium with the possibility for each ion to be in either one of the two phases—in the ion-exchange matrix proper or in the aqueous pore. 

On the other hand, the ionized forms, which tend to be less lipid soluble, cannot diffuse across tire lipid phase of the cell membrane. Ionized molecules may also repelled from the cell surface by groups with similar charge, or may be attracted to it and held there by groups with opposite charge. Ionized drug forms are, sometimes, unable to be filtered even through the aqueous pores of the membranes due to their own size or to the size they attain after the attraction of water molecules. 

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