Permeability and absorbency

Aside from permeability and absorbency complications, other universal concerns of helium leak detection are factors such as source operating pressure, spraying patterns (for tracer-probe technique), response time, clean-up time, and cold trap usage. Pump use and general helium leak detector maintenance operations are also fairly universal. 

Wood that has survived archaeological time and conditions will undoubtedly have gluing properties that are, in varying degrees, different from those of fresh unmodified wood. Bulk strength may have been reduced and fluid permeability and absorbency increased. Surfaces, in particular, may have strength and wettability that have been altered by aging. Treatment with consolidants and dimensional stabilizers may have been necessary, and this will often leave surface residues and reduce permeability and absorbency. 

Insoluble corrosion prodiic ts may be completely impeivious to the corroding liquid and, therefore, completely protective or they may be quite permeable and allow local or general corrosion to proceed unhindered. Films that are nonuniform or discontinuous may tend to localize corrosion in particular areas or to induce accelerated corrosion at certain points by initiating electrolytic effects of the concentration-cell type. Films may tend to retain or absorb moisture and thus, by delaying the time of drying, increase the extent of corrosion resulting from exposure to the atmosphere or to corrosive vapors. 

PAMPA is typically used to make a prediction of the passive, transcellular absorption of a compound. Compounds which may be absorbed by a paracellular mechanism or may be substrates for active transport (uptake or efflux) are usually better assessed in a cell based system. A combination of assays can be applied to gain a greater understanding of the permeability and transport properties of a compound. 

Drug candidates that are intended for oral dosing need to have good ADME properties so that they can be dosed once or twice daily. The drug should be well absorbed, survive first pass metabolism, and have sufficiently low clearance. At the lead identification stage, the primary in vitro ADME assays employed are those that assess permeability and metabolic stability. There are a variety of assays available for both parameters, as described in the previous chapter. 

Figure 5 Correlation of the fraction of dose absorbed with rat permeability. The rat permeability data were determined using the rat perfusion model. Considering the difference between the human permeability and the rat permeability, a scale factor was used to calculate the absorption number in Eq. (8). (Ref. 34 with kind permission from Plenum Publishing Corporation, New York.)...

Many academic and industrial laboratories have shown that the drug permeability measured in Caco-2 cell monolayers can be used to predict the oral absorption of drugs in humans. Various datasets have therefore been used to establish correlations between Caco-2 permeability and the fraction absorbed orally in humans [85, 86, 96]. Taken together, these studies show good predictability, though with a relatively wide variation in the appearance of correlation profiles between different laboratories [86]. These studies emphasize the need to establish correlations and standardization procedures in each laboratory. 

Compounds absorbed by active uptake mechanisms (e.g., glucose and Gly-Pro) and compounds known to be substrates for efflux transport (e.g., digoxin, verapamil) were also included in the list. The applied concentration (10-500 pM) only had minor effects on the permeability values. Thus, the choice of concentration was not critical for this set of compounds with respect to the relationship between permeability and fraction absorbed in humans. Changing the pH on the apical donor side had significant effects on the Papp values of several compounds, the effects being in agreement with the acid-base properties of the compounds. The... 

Fig. 7.10. Correlation between in vivo Peff (determined with the Loc-I-Gut technique in humans) and octanol/buffer (pH 6.5) distribution coefficients for several common drugs. Drugs with octanol/buffer (pH 6.5) distribution coefficients >0 are highly permeable and well absorbed in humans (fa > 90%).

In the current era with widespread problems of poor solubility [4] a compound (drug) with average permeability and a projected clinical potency of 1 mg kg-1 needs a minimum aqueous solubility of 50-100 jug mL-1 to avoid the use of nonstandard solubility fixing formulation technology. The guidelines published by Pfizer s Curatolo on maximum absorbable dose are an excellent guide for the combination of permeability, solubility and potency required in an orally active drug [8],... 

According to the FDA BCS guideline, measurements of the permeability and fraction dose absorbed of a drug can be made by mass balance, absolute bioavailability or intestinal perfusion methods. The intestinal permeability of a drug can be determined by ... 

It is important to recognize that the in vitro permeability obtained in cell mono-layers (such as Caco-2 models) should be considered as a qualitative rather than quantitative value. Especially poor are predictions of fraction dose absorbed for carrier-mediated drugs with low Caco-2 permeability and predictions of high fraction dose absorbed in humans [7, 20, 42, 48, 51]. However, it is possible to establish a reasonably good IVIVC correlation when passive diffusion is the dominating absorption mechanism. 

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyl-transferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an impaired capacity to sulfate phenol (Ramakrishna et al. 1991), which may increase the amount of unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater surface area. A study in which 10-day-old rats were more sensitive to lethality following oral exposure to phenol than 5-week-old or adult rats (Deichmann and Witherup 1944) further suggests that the young may be more sensitive to phenol. (For a more detailed discussion please see Section 2.6.) Because phenol is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol. Individuals with kidney or liver diseases that impair metabolism or excretion of phenol and phenol metabolites may be more susceptible to phenol. 

EVOHs absorb water, the more so as the VOH rises, which increases gas permeability and necessitates protection of EVOH by coating with another thermoplastic that is insensitive to moisture. 

Many companies have tried to develop peptidic renin inhibitors. Unfortunately these are rather large molecules and not unexpectedly poor absorption was often observed. The role of physicochemical properties has been discussed for this class of compounds. One of the conclusions was that compounds with higher lipophilicity were better absorbed from the intestine [29]. Absorption and bile elimination rate are both MW-dependent. Lower MW results in better absorption and less bile excretion. The combined influence of molecular size and lipophilicity on absorption of a series of renin inhibitors can be seen from Figure 1.7. The observed iso-size curves are believed to be part of a general sigmoidal relationship between permeability and lipophilicity [30-31] (for further details see Chapter 3). 

Kinetic solubility This pragmatic approach starts with a concentrated compound solution in pure DM SO further diluted in a buffer medium. The amount of compound in solution is measured after a few minutes incubation either by recording its UV absorbance (with or without a chromatographic step) or precipitate formation using an optical method (turbidimetry, nephelometry or flow cytometry). This approach mimics the typical path of the compound in biochemical, cellular assays or in vivo animal models. Kinetic solubility usually serves as a quality filter prior to cell based assays (see paragraphs on solubility, permeability and cellular assays). 

Figure 3.1 Correlation between passive permeability and in vivo BAV in Sprague Dawley rats (N=m). The PAMPA F(%) values in the y-axis were derived from the passive permeability measurements in a PAMPA assay [19] using a calibration curve with reference compounds of known fraction absorbed.

Pharmacokinetics plays a very important role in the manner in which opioids are abused. Morphine and many of its derivatives are slowly and erratically absorbed after oral administration, which makes this route suitable for long-term management of pain but not for producing euphoria. In addition, opioids undergo considerable first-pass metabolism, which accounts for their low potency after oral administration. Heroin is more potent than morphine, although its effects arise primarily from metabolism to morphine. The potency difference is attributed to heroin s greater membrane permeability and resultant increased absorption into the brain. 

Volatile irritants such as ammonia and chlorine initially cause constriction of the bronchioles. These two gases are water soluble, are absorbed in the aqueous secretions of the upper airways of the respiratory system, and may not cause permanent damage. Irritant damage may however lead to changes in permeability and edema, the accumulation of fluid. Some irritants such as arsenic compounds cause bronchitis. 

Uses of gelatin are based on its combination of properties reversible gel-to-sol transition of aqueous solution viscosity of warm aqueous solutions ability to act as a protective colloid water permeability and insolubility in cold water, but complete solubility in hot water. It is also nutritious. These properties are utilized in the food, pharmaceutical, and photographic industries. In addition, gelatin forms strong, uniform, clear, moderately flexible coatings which readily swell and absorb water and are ideal for the manufacture of photographic films and pharmaceutical capsules. 

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