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Permeation enhacer-cyclodextrin-permeability: It is well known that cyclodextrins can enhance the permeation of poorly Masson et al. (1999) soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in an excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins cannot be explained due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, that is, by decreasing the barrier function of the lipophilic membrane. In the present work, we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane-controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by a simple mathematical equation where the properties of the system are expressed in terms of two constants Pu/Kd and Mi/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution toward the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.

Permeation model-solute flux: Methyl- and propylparaben flux from various alcohol donors through polydimethylsiloxane Twist and Zatz (1988)

membranes was investigated. Flux from saturated alcohol vehicles was markedly increased relative to water and glycol systems. The uptake of neat alcohol, a measure of solvent membrane interaction, gave a good rank order correlation to the flux data for a particular paraben. The major influence of the alcohols was an increase in membrane solubility of paraben, with a smaller effect on the diffusion coefficient. High paraben donor solubility indirectly reduced the solvent-membrane interaction leading to attenuated flux. Paraben membrane solubility was influenced by the amount of alcohol sorbed from saturated systems and the affinity of the paraben for the alcohol. This conforms to the concept of imbibed alcohol molecules being organized into clusters. The alteration in barrier properties of the membrane was found to require the presence of sorbed alcohol and was reversible upon removal of the solvent.

Permeation-skin-gas chromatography (GC)/MS: A silastic membrane was coated onto a fiber to be used as a permeation Xia et al. (2003) membrane. The MCF was immersed in the donor phase to partition the compounds into the membrane. At a given partition time, the MCF was transferred into a GC injector to evaporate the partitioned compounds for quantitative and qualitative analyses. This technique was developed and demonstrated to study the percutaneous permeation of a complex mixture consisting of 30 compounds. Each compound permeated into the membrane was identified and quantified with GC/MS. The standard deviation was less than 10% in 12 repeated permeation experiments. The partition coefficients and permeation rates in static and stirred donor solutions were obtained for each compound. The partition coefficients measured by this technique were well correlated (R2 = 0.93) with the reported octanol/water partition coefficients. This technique can be used to study the percutaneous permeation of chemical mixtures. No expensive radiolabeled chemicals were required. Each compound permeated into the membrane can be identified and quantified. The initial permeation rate and equilibrium time can be obtained for each compound, which could serve as characteristic parameters regarding the skin permeability of the compound.

Permeation-solubility-intestinal absorption: Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/ pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared three theoretical scenarios: the GIT pH range overlapping: (/) only the salt solubility curve, (//) the salt and base solubility curves, or (///) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into two of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at two pHs, to permit calculation of the whole solubility/pH profile.

Pharmacokinetic-physical property relationship review: The ADME (absorption and distribution in the body, metabolism and elimination from the body) profile of a drug determines its pharmacokinetics in the body. Modern drug design includes the modeling of pharmacokinetically favorable behavior. The most interesting pharmacokinetic parameters that are of concern are intestinal absorption, BBB passage, and metabolism. Traditionally, experimental parameters, such as partition coefficients and chromatographic capacity factors have been used for the estimation of intestinal absorption or BBB passage of newly synthesized compounds. Several studies have shown a sigmoidal relationship between intestinal absorption and lipophilicity. The latter is usually expressed by the apparent partition coefficient log D in a biphasic system at physiological pH or by the affinity to a lipophilic phase determined by chromatographic techniques. In contrast, structure-based descriptors need no experimental investigation of the compound studied. The most relevant descriptors give information on hydrogen-bonding characteristics and molecular volume. In recent years, attempts have been made to recognize substrates for MDR proteins by their structure characteristics without crucial success. There is evidence that MDR is not only driven by direct protein-substrate recognition, but also by the behavior of the compound in the lipid environment of the protein.

Physiologic model-physiologically based pharmacokinetic model (PB/PK): A physiologically based model for Gl transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (Fabs) of both neutral and ionizable compounds on the two main physico-chemical input parameters [the intestinal permeability coefficient (Pint) and the solubility in the intestinal fluids (Sint)] as well as the physiological parameters, such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between Fabs and Pint. In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound's membrane affinity and MWwas used successfully in combination with the PB-PK model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds.

Hendriksen et al. (2003)

Kramer and Wunderli-Allenspach (2001)

Willmann et al. (2004)

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