Water layer permeability

Figure 7.8 Permeation of drugs through oil-soaked microfilters comparisons to Caco-2 permeabilities (dashed curves) [546] (a) oil-free (untreated hydrophilic) filters (b) unstirred water layer permeability versus log MW (c) octanol-soaked (impregnated) filters (d) isopropylmyristate-soaked filters.

The UWL permeability is nearly the same for drugs of comparable size, and is characterized by the water diffusivity (Daq) of the drug divided by twice the thickness of the layer (ftaq), Pu = Aiq / (2 h.Aq), in a symmetric permeation cell [40], The unstirred water layer permeability can be determined experimentally in a number of ways based on pH dependency of effective permeability [25,509,535-538], stirring rate dependence [511-514,552,578], and transport across lipid-free microfilters [25,546],... 

Figure 7.34 Permeability-pH profiles of ketoprofen (a) log-log plot solid curve represents effective permeability, and the dashed curve is the membrane permeability, calculated by Eq. (7.53). The latter curve levels off at the intrinsic permeability, Pq. The effective curve levels off to approximately the unstirred water layer permeability, Pu. (b) Direct plot the inset curve for the fraction neutral substance levels of at 100% (scale not shown). [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

TABLE 7.15 Intrinsic Permeabilities and Unstirred Water Layer Permeabilities Determined from Iso-pH Dependence of Effective Permeabilities 2% DOPC in Dodecane... 

Carbamazepine, antipyrine, terbutaline, and hydrochlorothiazide were treated as neutral molecules. Their effective permeabilities were corrected for the unstirred water layer using estimated unstirred water layer permeabilities, determined by the other molecules of similar lipophilicities and size. 

When the intrinsic PAMPA data (P0) are corrected for the appropriate unstirred water layer permeability (P "), the unified relationship between the biological barrier data (Papp) and the artificial membrane data is ... 

Water-Vapor Permeability. Water-vapor permeabiUty depends on the polymer used for the coating layer and its stmcture. Vinyl-coated fabrics have Httie water-vapor permeabiUty due to the coating layer. Although polyurethane polymer is water-vapor permeable, urethane-coated fabrics also have low permeabiUty values due to their soHd layer stmcture. On the other hand, man-made leathers have good permeabiUty values as high as that of leather due to their porous layer stmcture. The permeabiUty of grain-type is lower than that of suede-type, influenced by finishing method. 

Multilayered materials owe their properties and behavior to the properties of and the interactions between the components (5). Each of the two or more components contributes its particular property to the total performance of the multilayered material. For example, in Pouch 1, Table II, the aluminum foil provides high oxygen and water vapor permeability resistance, poly (ethylene terephthalate) provides structural strength and stiffness, and the ethylene-butene copolymer provides a heat sealable layer. If the components of the multilayered materials interact then the whole would be something different than the sum of its parts. In other words, the properties of the components of the multilayered materials are not independent of one another but rather are interdependent. 

Intrinsic Permeability, Permeability-pH Profiles, Unstirred Water Layers (UWL), and the pH Partition Hypothesis... 

The membrane permeabilities Pm may be converted to intrinsic permeabilities P(h when the pKa is taken into consideration. An ionizable molecule exhibits its intrinsic permeability when it is in its uncharged form and there is no water layer resistance. The relationship between Pm and P0 is like that between the pH-dependent apparent partition coefficient (log Kd) and the true partition coefficient (log Kp), respectively. This relationship can be rationalized by the mass balance. Take, for example, the case of a monoprotic acid, HA. The total substance concentration is... 

The method preferred in our laboratory for determining the UWL permeability is based on the pH dependence of effective permeabilities of ionizable molecules [Eq. (7.52)]. Nonionizable molecules cannot be directly analyzed this way. However, an approximate method may be devised, based on the assumption that the UWL depends on the aqueous diffusivity of the molecule, and furthermore, that the diffusivity depends on the molecular weight of the molecule. The thickness of the unstirred water layer can be determined from ionizable molecules, and applied to nonionizable substances, using the (symmetric) relationship Pu = Daq/ 2/iaq. Fortunately, empirical methods for estimating values of Daq exist. From the Stokes-Einstein equation, applied to spherical molecules, diffusivity is expected to depend on the inverse square root of the molecular weight. A plot of log Daq versus log MW should be linear, with a slope of —0.5. Figure 7.37 shows such a log-log plot for 55 molecules, with measured diffusivities taken from several... 

Permeability is a property closely tied to the environment of the epithelial cell surface. There is little point in measuring permeability at pH 1.7, if the microclimate barrier has pH >5 and <8, averaging 6. An in vitro permeability screen based on donor pH 5.0-7.4 and acceptor pH 7.4 seems about right. It will be useful to correct the data for the unstirred water layer effect, using computational methods. 

Previously, the unstirred water layer (UWL) adjacent to the intestinal lining was considered to be the rate-limiting step for intestinal Peff of high-permeability compounds [27, 73], However, several in vivo studies have clearly reported that the thickness of this UWL is significantly thinner than was previously assumed, since... 

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... 

In the same way, o-nitrophenyl octyl ether (o-NPOE) was immobilized on polycarbonate (PC) filters and the apparent permeability measured after 5 h incubation time was correlated to log Pnpoe for a series of reference compounds (log Pnpoe ranging from —1 to 3.6) [90]. Lipophilicity values in the alkane/water system were also determined using PAMPA with hexadecane-PC coated filters [89]. In this case, a correlation was found between intrinsic permeability (log Pq, permeability corrected for ionization and for unstirred water layer contribution, which particularly affects permeability of lipophilic compounds) and log P ik. However, log Pq is obtained from the knowledge of the pJC, value(s) and the permeability pH profile and therefore requires the full permeability pH profile to be measured for each compound, which negatively impacts the assay throughput. 

The layer of water adjacent to the absorptive membrane of the enterocyte is essentially unstirred. It can be visualized as a series of water lamellas, each progressively more stirred from the gut wall toward the lumen bulk. For BCS class 2 compounds the rate of permeation through the brush border is fast and the diffusion across the unstirred water layer (UWL) is the rate-limiting step in the permeation process. The thickness of the UWL in human jejunum was measured and found to be over 500 pm [3]. Owing to its thickness and hydrophilicity, the UWL may represent a major permeability barrier to the absorption of lipophilic compounds. The second mechanism by which the UWL functions act as a barrier to drug absorption is its effective surface area. The ratio of the surface area of the UWL to that of the underlying brush border membrane is at least 1 500 [4], i.e., this layer reduces the effective surface area available for the absorption of lipophilic compounds and hence impairs its bioavailability. 

Fig. 4.9 (a) Logarithm of the apparent permeability coefficient, for perfusion experiments in rats (filled symbols) and Caco-2 (empty symbols) versus logarithm of the intrinsic permeability coefficients based on PAMPA. (b) The unstirred water layer effect in the Caco-2 data. 

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