Barrier membranes

The correlation coefficient for this equation was 0.994. Such a paraboHc dependence of activity on the partition coefficient may reflect partitioning of the dmg through several membrane barriers, which enabled the dmg to reach its site of action. 

A fundamental difference exists between the assumptions of the homogeneous and porous membrane models. For the homogeneous models, it is assumed that the membrane is nonporous, that is, transport takes place between the interstitial spaces of the polymer chains or polymer nodules, usually by diffusion. For the porous models, it is assumed that transport takes place through pores that mn the length of the membrane barrier layer. As a result, transport can occur by both diffusion and convection through the pores. Whereas both conceptual models have had some success in predicting RO separations, the question of whether an RO membrane is truly homogeneous, ie, has no pores, or is porous, is still a point of debate. No available technique can definitively answer this question. Two models, one nonporous and diffusion-based, the other pore-based, are discussed herein. 

Equation 7 shows that as AP — oo, P — 1. The principal advantage of the solution—diffusion (SD) model is that only two parameters are needed to characterize the membrane system. As a result, this model has been widely appHed to both inorganic salt and organic solute systems. However, it has been indicated (26) that the SD model is limited to membranes having low water content. Also, for many RO membranes and solutes, particularly organics, the SD model does not adequately describe water or solute flux (27). Possible causes for these deviations include imperfections in the membrane barrier layer, pore flow (convection effects), and solute—solvent—membrane interactions. 

Lead tetramethyl and lead tetraethyl are covalent lipophilic liquids of low water solubility. Certain inorganic forms of lead, for example, lead tetrachloride, have similar properties, but other forms such as lead nitrate and lead dichloride are ionic and water soluble. Covalent and lipophilic forms of lead, like lipophilic forms of organomercury and organotin, can readily cross membranous barriers such as the... 

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.]. 

Permeability-pH profiles, log Pe - pH curves in arhficial membrane models (log Pjpp - pH in cehular models), generally have sigmoidal shape, similar to that of log Dod - pH cf. Fig. 3.1). However, one feature is unique to permeabihty profiles the upper horizontal part of the sigmoidal curves may be verhcally depressed, due to the drug transport resistance arising from the aqueous boundary layer (ABL) adjacent to the two sides of the membrane barrier. Hence, the true membrane contribution to transport may be obscured when water is the rate-limiting resistance to transport. This is especially true if sparingly soluble molecules are considered and if the solutions on either or both sides of the membrane barrier are poorly stirred (often a problem with 96-well microhter plate formats). 

Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier. Usually this barrier is an insoluble polymer. In general, two types or subclasses of diffusional systems are recognized reservoir devices and matrix devices. These will be considered separately. 

Figure 2.1 Transport model diagram, depicting two aqueous cells separated by a membrane barrier. The drug molecules are introduced in the donor cell. The concentration gradient in the membrane drives the molecules in the direction of the acceptor compartment. The apparent partition coefficient, Kd = 2. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

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]. 

The equations used to calculate permeability coefficients depend on the design of the in vitro assay to measure the transport of molecules across membrane barriers. It is important to take into account factors such as pH conditions (e.g., pH gradients), buffer capacity, acceptor sink conditions (physical or chemical), any precipitate of the solute in the donor well, presence of cosolvent in the donor compartment, geometry of the compartments, stirring speeds, filter thickness, porosity, pore size, and tortuosity. 

Figure 7.17 shows the asymmetry ratios of a series of compounds (acids, bases, and neutrals) determined at iso-pH 7.4, under the influence of sink conditions created not by pH, but by anionic surfactant added to the acceptor wells (discuss later in the chapter). The membrane barrier was constructed from 20% soy lecithin in dodecane. All molecules show an upward dependence on lipophilicity, as estimated by octanol-water apparent partition coefficients, log KdaA). The bases are extensively cationic at pH 7.4, as well as being lipophilic, and so display the highest responses to the sink condition. They are driven to interact with the surfactant by both hydrophobic and electrostatic forces. The anionic acids are largely indifferent... 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Membrane banners are applied to the exterior of the foundation and also beneath the floor slab during construction. Materials used for the membrane barriers range from coextruded poly olefin to polyvinyl chloride to foil sheets with many other materials in between. All membrane barriers must have the edges sealed to prevent radon from migrating around the edges and back into the building. 

Tetra(o-aminophenyl)porphyrin, H-Co-Nl TPP, can for the purpose of electrochemical polymerization be simplistically viewed as four aniline molecules with a common porphyrin substituent, and one expects that their oxidation should form a "poly(aniline)" matrix with embedded porphyrin sites. The pattern of cyclic voltammetric oxidative ECP (1) of this functionalized metal complex is shown in Fig. 2A. The growing current-potential envelope represents accumulation of a polymer film that is electroactive and conducts electrons at the potentials needed to continuously oxidize fresh monomer that diffuses in from the bulk solution. If the film were not fully electroactive at this potential, since the film is a dense membrane barrier that prevents monomer from reaching the electrode, film growth would soon cease and the electrode would become passified. This was the case for the phenolically substituted porphyrin in Fig. 1. 

Possible driving forces for solute flux can be enumerated as a linear combination of gradient contributions [Eq. (20)] to solute potential across the membrane barrier (see Part I of this volume). These transbarrier gradients include chemical potential (concentration gradient-driven diffusion), hydrostatic potential (pressure gradient-driven convection), electrical potential (ion gradient-driven cotransport), osmotic potential (osmotic pressure-driven convection), and chemical potential modified by chemical or biochemical reaction. 

Mucosal brush border membrane vesicles and basolateral membrane vesicles can be isolated to study solute uptake across specific enterocyte boundaries. These more isolated vesicle systems allow for investigation of solute transport across a particular membrane barrier and permit separation of membrane trans-... 

Fig. 7.1. The intestinal permeability of drugs in vivo is the total transport parameter that may be affected by several parallel transport mechanisms in both absorptive and secretory directions. Some of the most important transport proteins that may be involved in the intestinal transport of drugs and their metabolites across intestinal epithelial membrane barriers in humans are displayed.

Polythene and mylar sheeting laid over the suspended wooden floor reduced the concentrations of radon decay products, but not below the reference level. This technique was only partially successful because of the difficulty of effecting good seals to the walls, indicating the care needed to remedy high radon levels with membrane barriers. 

There appear to be two major ways by which ionophores aid ions to cross membrane barriers. Ionophores such as valinomycin and nonactin enclose the cation such that the outside of the complex is quite hydro-phobic (and thus lipid-soluble). The transport behaviour thus involves binding of the cation at the membrane surface by the antibiotic, followed by diffusion of the complexed cation across the membrane to the opposite surface where it is released. Such carrier type ionophores can be very efficient, with one molecule facilitating the passage of thousands of ions per second. A prerequisite for efficient transport by this type of ionophore is that both the kinetics of complex formation and dissociation be fast. 

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