Membrane barrier permeation

To predict membrane barrier permeation by drugs we developed an algorithm that determines the molecular axis of amphiphilicity and the cross-sectional area, ADcalc, perpendicular to this axis. 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

Using liposomes made from phospholipids as models of membrane barriers, Chakrabarti and Deamer [417] characterized the permeabilities of several amino acids and simple ions. Phosphate, sodium and potassium ions displayed effective permeabilities 0.1-1.0 x 10 12 cm/s. Hydrophilic amino acids permeated membranes with coefficients 5.1-5.7 x 10 12 cm/s. More lipophilic amino acids indicated values of 250 -10 x 10-12 cm/s. The investigators proposed that the extremely low permeability rates observed for the polar molecules must be controlled by bilayer fluctuations and transient defects, rather than normal partitioning behavior and Born energy barriers. More recently, similar magnitude values of permeabilities were measured for a series of enkephalin peptides [418]. 

To reach the reductive step of the azo bond cleavage, due to the reaction between reduced electron carriers (flavins or hydroquinones) and azo dyes, either the reduced electron carrier or the azo compound should pass the cell plasma membrane barrier. Highly polar azo dyes, such as sulfonated compounds, cannot pass the plasma membrane barrier, as sulfonic acid substitution of the azo dye structure apparently blocks effective dye permeation [28], The removal of the block to the dye permeation by treatment with toluene of Bacillus cereus cells induced a significant increase of the uptake of sulfonated azo dyes and of their reduction rate [29]. Moreover, cell extracts usually show to be more active in anaerobic reduction of azo dyes than whole cells. Therefore, intracellular reductases activities are not the best way to reach sulfonated azo dyes reduction the biological systems in which the transport of redox mediators or of azo dye through the plasma membrane is not required are preferable to achieve their degradation [13]. 

Pharmaceutical scientists assess and express drug permeation across membrane barriers in terms of flux. Flux measures the molar unit of a drug that permeates a resistant barrier (e.g., skin or gastrointestinal epithelial cells) per unit time and surface area (Box 13.1). Permeation enhancers, such as alcohols and surfactants, increase flux by modulating resistance factors that counteract drug diffusion across barriers at the site of administration. 

Pervaporation is a membrane separation process in which a dense, non-porous membrane separates a liquid feed solution from a vapour permeate (Fig. 19.2c). The transport across the membrane barrier is therefore based, generally, on a solution-difliision mechanism with an intense solute-membrane interaction. It... 

Fig. 19.3 The solution-diffusion transport model in pervaporation. a Solution of compounds from the feed phase into the membrane surface, b Diffusion across the membrane barrier, c Desorption from the membrane permeate (downstream) side into the permeate phase...

Several in vitro assays using filter immobilized artificial membranes exist for the estimation of permeability (Parallel artificial membrane permeation assay, PAMPA). In these assays the permeation of a compound is followed directly by estimating the amount of compound on either side of the membrane barrier. The results of these experiments are expressed as permeability values rather than lipophilicity values. 

On the other hand, PAMPA is a purely artificial method and PAMPA membranes do not reassemble real lipid bilayer structures as barriers for permeation but much thicker barriers. The thickness and material of the supporting PVDF filters also influences artificially the permeation of compounds depending on the lipophilicity of the compounds more than the thin polycarbonate filter does in CACo2 experiments. Also the best choice of membrane constituents for PAMPA experiments is still under investigation and it seems that it will depend a lot on the goal of the PAMPA experiment which membrane is used (e.g. blood brain barrier permeation or intestinal absorption). One has to take into account that PAMPA today is a summary term on a lot of different methods applied in different laboratories using different membrane constituents, sink conditions, permeation times etc., which makes inter laboratory comparison difficult. 

In membrane processes, a solute is defined as the chemical species which does not selectively permeate through the membrane barrier and thereby getting enriched on the high-pressure side of the membrane. Permeate refers to the chemical... 

Blood-brain barrier permeation molecular parameters governing passive diffusion. The Journal of Membrane Biology, 165, 201-211. 

Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distribution, metabolism, and excretion. The biodisposition of a drug involves its permeation across cellular membrane barriers. 

The processes of distribution of a drug from the systemic circulation to organs and tissue involve its permeation through membrane barriers and are dependent on its solubility (recall that only nonionized drugs cross biomembranes), the rate of blood flow to the tissues, and the binding of drug molecules to plasma proteins. 

The performance of a cross-flow filter is primarily defined by its efficiency in permeating or retaining desired species and the rate of transport of desired species across the membrane barrier. Microscopic features of the membranes greatly influence the filtration and separation performance.f ... 

Since the cornea is a membrane barrier containing both lipophilic and hydrophilic layers, drugs possessing both lipophilic and hydrophilic properties permeate it most effectively. The optimal range for the octanol/buffer pH 7.4 distribution coefficient (log P) for corneal permeation is 2 to 3 (Schoenwald and Ward 1978), observed for a wide variety of drugs. 

In addition to this nonlinear relationship for the blood-brain barrier permeation of imidazolines, many other nonlinear lipophilicity relationships have been derived for buccal and gastrointestinal absorption, skin permeation, as well as blood-brain and blood-placenta barrier permeation (e.g., Eqs. (58) to (62) Fig. 7 [59,60,63,64] Barbiturates permeation through an organic membrane ... 

Figure 7 The permeation of barbiturates through an organic membrane, the gastric and intestinal absorption of carbamates, the blood-placenta transfer rate constants of various drugs, and the neurotoxicity of homologous primary alcohols, as a measure of blood-brain barrier permeation, follow nonlinear lipophilicity relationships (Eqs. (58)-(62)). (From Refs. 58,59,62,63.)...

In the perfusion-limited case, the permeation is relatively fast compared to perfusion of the tissue hed. This tends to occur when the harrier is thin or has many gaps, the drug has a low molecular weight and is near the optimal logP value, and the blood flow rate is not very high. Since permeation is relatively fast in this case, the plasma and the tissue on either side of the membrane barrier come into equilibrium in a very short period of time. It should be pointed out that at equilibrium, the concentration in the plasma and the tissue are not necessarily equal. At equilibrium, the plasma and tissue concentrations are related to one another by the relationship... 

The unique ability of hydrogen ions to move along hydrogen-bonded chains suggested a possible flux mechanism that would differentiate between the permeation of protons and other cations. Perhaps ions do not dissolve in the bilayer to cross the membrane. Instead, transient hydrated defects may be produced by thermal fluctuations in the lipid, and ions could then cross the membrane barrier by diffusion through the defects. If water molecules in the defects are associated by hydrogen bonding, protons could cross the... 

The relationship between membrane structure, membrane function, and cell physiology is an area of active, ongoing study. Our interest here is practical what are the basic mechanisms of drug movement through membranes and how can one best predict the rate of permeation of an agent through a membrane barrier To answer that question, this section presents rates of permeation measured in some common experimental systems and models of membrane permeation that can be used for prediction. 

Vapor permeation and pervaporation are membrane separation processes that employ dense, non-porous membranes for the selective separation of dilute solutes from a vapor or liquid bulk, respectively, into a solute-enriched vapor phase. The separation concept of vapor permeation and pervaporation is based on the molecular interaction between the feed components and the dense membrane, unlike some pressure-driven membrane processes such as microfiltration, whose general separation mechanism is primarily based on size-exclusion. Hence, the membrane serves as a selective transport barrier during the permeation of solutes from the feed (upstream) phase to the downstream phase and, in this way, possesses an additional selectivity (permselectivity) compared to evaporative techniques, such as distillation (see Chapter 3.1). This is an advantage when, for example, a feed stream consists of an azeotrope that, by definition, caimot be further separated by distillation. Introducing a permselective membrane barrier through which separation is controlled by solute-membrane interactions rather than those dominating the vapor-liquid equilibrium, such an evaporative separation problem can be overcome without the need for external aids such as entrainers. The most common example for such an application is the dehydration of ethanol. 

Vapor permeation (VP) and pervaporation (PV) are membrane separation processes whose only difference lies in the feed fluid being a vapor (VP) or a liquid (PV), respectively. This difference has impHcations for feed fluid handling as well as the nature of the transport phenomena occurring in the feed stream, as in VP the feed fluid is compressible whilst in PV it is effectively not however, this does not in any way affect the transport phenomena across and after the membrane barrier. For this reason, vapor permeation and pervaporation will be discussed simultaneously, with differences being expHcitly emphasized where necessary. 

Clearly, from Fig. 1, the solubility of a solute in an organic solvent correlates very well with the permeability of the Nitella membrane for that solute. But it is also clear that the correlation is only partial. Thus, of two solutes with the same partition coefficient the one with smaller molecular weight would seem to permeate faster. Solute size as well as hpid solubility are both important determinants of permeation rate. The particular solvent chosen, olive oil, seems however to be a very good model for the ability of the membrane barrier to discriminate between the various permeants, since the overall increase in permeability as the structure of the permeant is varied correlates closely with the increase in partition coefficient. Were the two parameters to be strictly linked all the data would fall on the line of unit slope in the figure, the line of identity. Later we shall see cases where the data do not support such a close similarity between certain membranes and model solvents. 

Eqn. 5 provides a very clear theoretical basis for the data of Fig. 1 (and similar data on other systems, as we shall see). The measured permeability coefficients for a set of solutes should parallel the measured partition coefficients, if the model solvent corresponds exactly in its solvent properties to the permeability barrier of the cell membrane. In addition, the molecular size of the solute is very likely to be an important factor as it will affect the diffusion coefficients within the membrane barrier phase. Data such as those of Fig. 1 will convince us that we have in our chosen solvent a good model for the solvent properties of the membrane s permeability barrier. We can now calculate values of PLx/K for the various solutes, and obtain estimated values of the intramembrane diffusion coefficient, and are in a position to study what variables influence this parameter. Fig. 3 is such a study in which data from Fig. 1 are plotted as the calculated values of f>n,c,n/A.t (calculated as P/K) against the molecular weight of the permeating solute. The log/log plot of the data has a slope of — 1.22, which means that one can express the dependence of diffusion coefficient on molecular weight (A/) in the form where... 

The fastest growing desalination process is a membrane separation process called reverse osmosis (RO). The most remarkable advantage of RO is that it consumes little energy since no phase change is involved in the process. RO employs hydraulic pressure to overcome the osmotic pressure of the salt solution, causing water-selective permeation from the saline side of a membrane to the freshwater side as the membrane barrier rejects salts [1-4], Polymeric membranes are usually fabricated from materials such as cellulose acetate (CA), cellulose triacetate (CTA), and polyamide (PA) by the dry-wet phase inversion technique or by coating aromatic PA via interfacial polymerization (IFP) [5]. 

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