Measurement of permeability

The electrical resistivity (ER) is a more comprehensive measure of permeability than the Gurley number (air permeability), in that the measurement can be carried out in the actual electrolyte solution. Thus, the measurement reflects the compatibility of the separator with the electrolyte (e.g., the... 

Up to now we have focused on measurement of permeability and membrane retention at pH 7.4. Since the GIT covers a range of pH values, with pH 5-8 characterizing the small intestine, it is necessary to address the pH dependence of the transport of drug molecules. Even nonionizable molecules may be affected by pH dependence, since several biological membrane components themselves are ionizable (pKa values listed in Fig. 7.4). For example, with PS, PA, and DA (free fatty acid) undergoing changes in charge state in the pH 5-8 interval. In this section, we examine the consequences of pH dependence. 

The in vitro measurements of permeability by the cultured-cell or PAMPA model underestimate true membrane permeability, because of the UWL, which ranges in thickness from 1500 to 2500 pm. The corresponding in vivo value is 30-100 pm in the GIT and nil in the BBB (Table 7.22). The consequence of this is that highly permeable molecules are (aqueous) diffusion limited in the in vitro assays, whereas the membrane-limited permeation is operative in the in vivo case. Correcting the in vitro data for the UWL effect is important for both GIT and BBB absorption modeling. 

Avdeef, A., High-throughput measurements of permeability profiles, in van de Waterbeemd, H. Lennemas, H. Artursson, P. (eds.), Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability Wiley-VCH Weinheim, 2003 (in press)... 

Avdeef A (2002) Eligh-throughput measurement of permeability profiles. In Van de Waterbeemd H, Lennernas H, Arturrson P (Eds) Drug Bioavailability— Estimation of Solubility, Permeability and Absorption. Wiley-VCH, Weinheim, pp 46-70. 

There are a number of in vivo methods used to assess brain penetration each with their own benefits and limitations [41]. Much of the in vivo data comes from the brain blood ratio, which is not a direct measure of permeability and therefore is not directly comparable to in vitro permeability values [4]. 

Measurements of permeability and associated magnetic properties are usually made on toroids of uniform section when, to a close approximation, the flux density B is uniform throughout the material and lies entirely within it. In most practical applications the magnetic circuit is more complex, and variations in component section and permeability give rise to variations in flux density. Important effects arise from air gaps, which may be intentionally introduced or may be cracks or porosity. 

Measurement of permeability of porous media." Bull. Am. Assoc. Petro leum Geol., 18 161-190. 

In vitro techniques for the measuring of permeability are less labor- and cost-intensive compared with the more complex in situ and in vivo models. In addition, they are more suitable as screening models because they require smaller quantities of test compound. The capacity of an in vitro system to predict permeability across a biologic barrier depends on how closely the model resembles the in vivo system (8, 23). 

The selection and preparation of sites for any of these gas stores is a fairly delicate process, because tightness can rarely be guaranteed on the basis of geological test drillings and modelling. The detailed properties of the cavity will not become fully disclosed until the installation is complete. The ability of the salt cavern to keep an elevated pressure may turn out not to live up to expectations. The stability of a natural rock cave, or of a fractured zone created by explosion or hydraulic methods, is also imcertain until actual full-scale pressure tests have been conducted. For the aquifers, the decisive measurements of permeability can only be made at a finite number of places, so surprises are possible due to rapid permeability change over small distances of displacement (Sorensen, 2004a). 

The pressure drop across the initial fixed bed (or final previously aerated bed) is a measure of permeability kp as defined by Darcy... 

J.F. Quinson, N. Mameri, L. Guihard and B. Bariou, The study of the swelling of an ultrafiltration membrane under the influence of solvents by thermoporometry and measurement of permeability. /. Membr. Sci., 58 (1991) 191. 

Another approach to human bioavailability estimation is based on in vitro data using Caco-2 as a measure of permeability and human liver microsomes for metabolism estimates. These data are combined in a graphical method to get a rough estimate of human oral bioavailability [22]. In principle, but not yet proven, this method could also be applied by using calculated permeability and metabolic stability. 

Permeability is perhaps the most widely studied of the biological components of Figure 16.5 and as a result has led to a number of in silico models of this component [48], There are various experimental systems designed to give some measure of permeability ranging in complexity from partition into liposomes to permeability across Caco-2 cells (see Chapter 7). In silico models of Caco-2 cell permeability have been constructed [49], but the question may be asked why model the model of human absorption [50]. It may be better to measure, and make models of, more fundamental factors that affect permeability. 

In vitro experiments can sometimes provide valuable insight into what is happening in vivo that is limiting oral bioavailability. The typical experiments, often employed in tandem, to understand bioavailablilty are determinations of compound solubility, membrane permeability, and stability in subcellular fractions. The membrane permeability assays that are most often employed are either a measurement of permeability through an artificial membrane (Parallel artificial membrane permeability assay, PAMPA, is the most common technique) or a cell monolayer (Caco-2, a human colon carcinoma-derived cell line, is the most common cell monolayer). The subcellular fractions most often employed are plasma (for ester-containing compounds) and liver microsomes with the addition of either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or uridine diphosphoglucuronic acid (UDPGA) as cofactor. 

There are a number of useful in vitro measures of permeability that can be used to assess how well a given molecule will be absorbed. One of the most simple is the permeation of molecules through artificial (hexadecane) membranes (referred to as PAMPA studies). These measure transcellular permeation through bulk diffusion in systems that avoid the complexity of active transport. With these types of assays, compounds can be ranked on the basis of lipid permeation alone this can be a useful gauge of ability to penetrate the gut intestinal wall. 

The basis of this method is the measurement of permeability of a packed bed of powder to a laminar gas flow. The determination of permeability can be made either at continuous, steady-state... 

Direct measurements of permeabilities in unconsolidated marine sediments are difficult, and only few examples are published. They confine to measurements on discrete samples with a specially developed tool (Lovell 1985), to indirect estimations by resistivity measurements (Lovell 1985), and to consolidation tests on ODP cores using a modified medical tool (Olsen et al. 1985). These measurements are necessary to correct for the elastic rebound (MacKillop et al. 1995) and to determine intrinsic permeabilities at the end of each consolidation step (Fisher et al. 1994). In Section 2.4.2 a numerical modeling and inversion scheme is described which estimates permeabilities from P-wave attenuation and dispersion curves (c.f. also section 3.6). 

---