Passive permeation

Euture electrotransport therapeutic systems will differ substantially from those just described. They will draw on advances in microelectronics and transdermal system technology to provide transdermal therapy for compounds with low passive permeation rates, patterned or pulsed dmg deHvery,... 

To sum up, lipophilicity is only one component of permeability, and thus any relationships found between passive permeation and log D] are reliable for the investigated series of compounds, but cannot be used to make general predictions. 

Summing up, the selected Caco-2 data contain qualitative permeability measurements for 450 related (but chemically diverse) compounds that had been either collected from the literature or measured experimentally in laboratories connected with our group. Penetrating compounds were indicated by a score of +1, whereas a score of —1 was attributed to compounds having little (if any) ability to penetrate the epithelial cells. Passive permeation was used as a basic assumption of the model. 

The use of artificial membranes to investigate passive permeation processes has a long history, going back more than 40 years [68], The parallel artificial membrane permeation assay (PAMPA) is an application of the filter-supported lipid membrane system [149] and was first introduced by Kansy and... 

In addition it was also suggested that cell lines that have limited expression of transporters (e.g., 2/4/Al) are of use in understanding passive permeability. Saturation of transporters or inhibition can also be used to understand the contribution of passive permeation and active transport. 

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]. 

Organ-specific permeation of a drug is one area currently extensively investigated. While passive permeation determines the baseline of pharmacokinetics for most... 

Since passive permeation into cells occurs on time scales of hours or less, nonpolar compounds that are somewhat recalcitrant (i.e., lasting for days or more in the environment) are probably not limited by their ability to enter microorganisms from surrounding aqueous media. This expectation is supported by the observations that the relative rates of dehalogenation of a series of a,m-dichlorinated alkanes by resting cells of Rhodococcus erythropolis Y2 paralleled the results using a purified... 

The experimental protocol involved three consecutive stages of treatment to the same HEM a first passive permeation stage, which lasted for 3 h, followed by a 2 h electrical treatment period during which electroporation or iontophoresis or both protocols were applied to the skin and finally a second passive stage (2 h) evaluated possible reversibility of skin barrier function following electrical treatment. 

Passive Permeation (Diffusion) through the Membrane Lipid Bilayer... 

Passive permeation (diffusion) through the lipid bilayer... 

Most drug substances and substances of interest to health and environmental risk assessors enter cells by passive permeation (diffusion). In this process, a substance dissolves in the membrane lipid bilayer, permeates through the membrane, and enters into the cytoplasm of the cell. The substance thus must be soluble in lipids. The process is passive because the rate and extent to which a substance will enter a cell by this means depends on its concentration outside and inside the cell. The net movement is from the region of higher concentration to that of lower concentration. Unlike the cell membrane, which is chiefly lipid, the extracellular and intracellular spaces separated by the membrane are aqueous. The higher the concentration of substance outside of the cell, and the more soluble the substance in the membrane lipid bilayer, the greater will be the tendency for the substance to diffuse across the membrane and enter the cytoplasm. The rate and extent of diffusion will decrease as the concentration of the substance inside the cell increases until, eventually, equilibrium is reached. 

If the water solubility of a substance is very low, an extracellular concentration sufficient to establish an adequate concentration gradient is unlikely. Consequently, little of the substance will permeate the membrane, even if it is lipid soluble. Hence, in addition to lipid solubility, water solubility is an important factor that controls the extent to which a substance can enter a cell by passive permeation. In fact, lipid-to-water partitioning, rather than lipid solubility or water solubility alone, is the more important factor governing a substance s ability to diffuse through cell membranes. Other factors that control the rate and extent to which a substance permeates a cell membrane are the thickness and surface area... 

Another important physicochemical parameter is the pKa, which describes the ionisation state of a compound at a given pH. The ionisation state of a compound in the different components of the gastro intestinal system (stomach, jejunum, ileum and colon) is crucial for the understanding of drug absorption (Dressman). Ionised compounds generally have better solubility, but passive permeation through the membrane is limited (Comer). 

In Section 3.2 we introduced the basic processes of advection, diffusion, and drift, by which material is transported in biophysical systems. In this chapter we focus on a specialized class of transport transport across biological membranes. Transport of a substance across a membrane may be driven by passive permeation, as described by Equation (3.60), or it may be facilitated by a carrier protein or transporter that is embedded in the membrane. Thus transport of substances across membranes mediated by transporters is termed carrier-mediated transport. The most basic way to think about carrier proteins or transporters is as enzymes that catalyze reactions that involve transport. 

The fluxes, governed by passive permeation, are computed in terms of total reactant concentrations ... 

All of these simple models have in common the fact that they are accessible to mathematical analysis, while more complex models are not. Yet whether one is dealing with idealized (analyzable) models or complex three-dimensional models, it is essential that the governing equations appropriately represent the underlying physical phenomena. To serve as a resource for this purpose, examples involving time-dependent and steady state transport, simple and facilitated diffusion, and passive permeations between regions were studied. 

Only a few laser scanning confocal microscopy (LSCM) studies have examined the passive permeation pathways of molecules across the skin. Cullander and Guy [36] showed that calcein, a multiply charged fluorophore, penetrates minimally into the SC of hairless mouse skin (HMS). Similar studies by Turner et al. [37a] have confirmed this observation. Indeed, it is the hydrophilic, charged nature of calcein that prevents its facile partitioning into the lipophilic intercellular spaces of the SC. Although some penetration of calcein into the SC intercellular domains, and into the pilary canal of the hair follicles, is observed, the total passive epidermal transport of calcein was negligible. 

With an experimental protocol in place that facilitated studies aimed at characterizing the porous permeation pathway, a systematic study of polar compound permeation through HEM was undertaken (Peck et al., 1994). As has already been described, there is a void in the literature with respect to the passive permeation of polar solutes through skin. The initial purpose of the studies outlined in this section was to add to the polar solute permeation database. An effort was again made to determine the degree to which the barrier characteristics of skin with respect to polar compounds approach, or deviate from, those of an ideal porous membrane. 

It is reasonable to expect that nonelectrolytes normally have to take off their tightly bound hydration shell, at least partly, before they passively permeate a lipid bilayer. This mechanism has been studied for glucose, where it was assumed that the number of bound water molecules correlates with the activation energy of the permeation process (7). 

Cholesterol affects a large variety of membrane properties in animal cells (39). It is involved in modifying dynamical membrane properties by reducing passive permeation, slowing down the lateral diffusion of molecules in fluid-like membranes, and speeding up diffusion in gel-phase membranes. It also affects bilayer properties by condensing the bilayer, which changes its elastic properties and promotes the order of phospholipid acyl chains in the hydrophobic membrane core. In this manner, cholesterol develops the formation of the liquid-ordered... 

The remarkable barrier function of the skin is primarily located in the stratum corneum (SC), the thin, outermost layer of the epidermis. The SC consists of several layers of protein-filled corneocytes (i.e., terminally differentiated keratinocytes) embedded in an extracellular lipid matrix. Attached to the outer cor-neocyte envelope are long-chain covalently bound cer-amides that interact with the lipids of the extracellular space. These lipids are composed primarily of free fatty acids, ceramides, and cholesterol arranged in multiple lamellae.f Passive permeation across the SC is believed to occur primarily via the intercellular... 

Figure 2.1. The pathways that a drug can take to cross the intestinal mucosa harrier. Pathway A is the transcellular route in which a drug passively permeates the cell membranes. Pathway B is the paracellular route the chug passively diffuses via the intercellular junctions. Pathway C is the route of active transport of the drug hy transporters. Pathway D is the route of drug permeation that is modified hy efflux pumps.

Biomimetic artifical membrane-paracellular pathways-Renkin function The purpose of this study was to construct and examine the prediction model for total passive permeation through the intestinal membrane. The paracellular pathway prediction model based on Renkin function (PP-RF) was combined with a bio-mimetic artificial membrane permeation assay (BAMPA), which is an in vitro method to predict transcellular pathway permeation, to construct the prediction model (BAMPA-PP-RF model). The parameters of the BAMPA-PP-RF model, for example, apparent pore radius and potential drop of the paracellular pathway, were calculated from BAMPA permeability, the dissociation constant, the molecular radius, and the fraction of a dose absorbed in humans consisting of 80 structurally diverse compounds. The apparent pore radius and the apparent potential drop obtained in this study were 5.61-5.65 A and 75-86 mV, respectively, and these were in accordance with the previously reported values. The mean square root error of the BAMPA-PP-RF model was 13-14%. The BAMPA-PP-RF model was shown to be able to predict the total passive permeability more adequately than BAMPA alone. 

After five days, dopamine, L-tryptophan, and l-DOPA passively permeated through the membrane as indicated by fittings with a first-order kinetic process equation. After seven days of co-culture, occludin localizes at EC periphery, dopamine does not cross the barrier to any further extent, while the transfer of L-tryptophan and l-DOPA fits well with a saturable Michaelis-Menten kinetic process, thus indicating the involvement of a specific carrier-mediated transport mechanism. Permeation studies confirmed that culture of ECs in the presence of neurons induces the characteristic permeability limitations of a functional BBB. 

Drugs are cleared from the vitreous primarily by two routes. The anterior route involves drainage into the anterior chamber and clearance with aqueous turnover via bulk flow. The posterior route involves either active or passive permeation across the retina and RPE and subsequent systemic dissipation (71,72). There is evidence that for some, highly lipophilic, compounds clearance via the retinal blood vessels may also play an important role (73). 

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