Absorption permeability

When a compound is crossing a membrane by purely passive diffusion, a reasonable permeability estimate can be made using single molecular properties such as log D 

Important progress in terms of higher throughput in ADME/PK work was realized recently by wider use of liquid chromatography/mass spectrometry (LC/MS), which has now become a standard analytical tool [26]. Flow NMR spectroscopy has become a routine method to resolve and identify mixtures of compounds and has found applications in drug metabolism and toxicology studies [27]. 

A rapid spectrofluorimetric technique for determining drag-serum protein binding in high throughput mode has been described [32]. 

P-glycoprotein-mediated efflux is a potential source of pecuHarities in drag pharmacokinetics, such as non-Hnearity. This includes dose-dependent absorption, drug-drag interactions, intestinal secretion and limited access to the brain. Assays are in development to quantify the interaction between transporters and drugs. One of the first is a 96-weU plate assay for P-gp binding [33, 34] and an MDRl ATPase test [35]. 

The balance between renal clearance and metabohsm is readily predicted by physicochemical properties [36]. Rate of metabolism and formation of metabolic products can be screened for, using Ever microsomal systems and mass spectrometry. The 

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Possible noninvasive routes for delivery of proteins include nasal, buccal, rectal, vaginal, transdermal, ocular, oral, and pulmonary. For each route of delivery there are two potential barriers to absorption permeability and enzymatic barriers. All of the... 

Keywords Isolated perfused lung Absorption Permeability Instillation Aerosolisation Drug disposition In vitro-in vivo correlation... 

Keywords Buccal Mucosa In vitro Absorption Permeability Culture... 

Toyobuku, H., Tamai, 1., Ueno, K. and Tsuji, A. (2003) Limited influence of P-glycoprotein on small-intestinal absorption of cilostazol, a high absorptive permeability drug. Journal of Pharmaceutical Sciences, 92, 2249-2259. 

From an analysis ofthe key properties of compounds in the World Drug Index (WDI), the now well-accepted rule-of-5 has been derived [136, 137]. It was concluded that compounds are most likely to have poor absorption when the molecular weight is more than 500, the calculated octanol/water partition coefficient (Clog P) is more than 5, number of H -bond donors is more than 5, and the number of H-bond acceptors is more than 10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The rule-of-5 should be seen as a qualitative absorption/permeability predictor [138], rather than a quantitative predictor [139]. The rule-of-5 is not predictive for bioavailability as sometimes mistakenly assumed. An important factor for bioavailability in addition to absorption is liver first-pass effect (metabolism). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [140,141]. 

A drug s absorption, as reflected in its bioavailability, is a fairly complex process, and although it is related to the drug structure, it is related in a complex manner. Failure to appreciate and understand these complexities, in an attempt to build models, may provide a prediction of marginal and low confidence. Both fraction absorbed and bioavailability are measures of the extent of absorption. Permeability, on the other hand, is related to the rate of absorption (20) ... 

Capillary absorption/ permeability to water EN 1062-3 Porous clay or calcium silicate bricks, mortar XC3 XC4 G Absorp. coeff. iv<0.1 kg m. h" ... 

With increasing importance being attached to the early detection of compounds likely to be problematic from an absorption, distribution, metabolism, and excretion (ADME) viewpoint, " at RPR we sought to apply computational measures for the prediction of intestinal absorption—a key requirement for an orally bioavailable compound—during the design of lead optimization libraries. To this end, we implemented the popular rule-of-5 criteria described by Lipinski et al. compound is deemed to fail the rule-of-5 check (and thereby to be possibly deficient from an oral absorption/permeability aspect) if it possesses two or more of the following features ... 

Once the drug is solubilized, it is absorbed through the intestinal walls and enters the systemic circulation for distribution. Although there are different possibilities for absorption, permeability through passive diffusion is the most important route followed. Here lipophilicity and size of the molecule play a very important role. A smaller sized neutral molecule is more likely to pass through the hydrophobic phospholipid membrane of the intestinal wall than a large, charged molecule. 

The use of a faster-growing cell line, MDCK (Madin-Darby canine kidney) cells, appears to be a good replacement for Caco-2 cells (Irvine et al. 1999). The parallel artificial membrane permeation assay (PAMPA) is a rapid in vitro assay, in which transcellular permeation is evaluated (Kansy et al. 1998). PAMPA may also be used to predict oral absorption, blood-brain barrier penetration, and human skin permeability (Fujikawa et al. 2007) by using QSAR models. To our knowledge, neither PAMPA, Caco-2 cell monolayers nor MDCK cells have been used to examine the absorption/permeability of the pyrethroids. The advantages and limitations of the Caco-2 model were reviewed by Artursson et al. (1996) and Delie and Rubas (1997). 

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