The highly mobile kava lactones permeated in the order: dihydromethisticin (40) > yangonin (37) > kavain (34) > methisticin (32) > desmethoxyyangonin (26), the numbers in parentheses being the measured effective permeabilities in units of 10(-6) cm/sec. By comparison, commercial drugs ranked: phenazopyridine (35) > testosterone (19) > propranolol (13) > ketoconazole (6.3) > piroxicam (2.2) > caffeine (1.7) > metoprolol (0.8) > terbutaline (0.01). In addition to permeability measurements, membrane retention of compounds was determined. More than 60% of yangonin, desmethoxyyangonin, ketoconazole, and phenazopyridine were retained by the artificial membranes containing phospholipids. Stirring during assay significantly increased the observed permeabilities for highly mobile molecules, but had minimal impact on the poorly permeable molecules. The influence of hydrogen bonding was explored by determining permeabilities using filters coated with dodecane, free of phospholipids. In the filter-IAM method, concentrations were determined by microtitre plate UV spectrophotometry and by LC-MS. HT was achieved with direct UV by the use of 96-well microtitre plate formats and with LC-MS by the use of cassette dosing (five-in-one).

Membranes-biologic-synthetic-comparison: Permeability coefficients of seven compounds belonging to a true homologous Diez-Sales et al. (1991) series (4-alkylanilines) through several different synthetic and biological membranes were assayed in a two-chamber diffusion cell. Permeability-lipophilicity relationships for the experimental data were established and compared in order to ascertain whether the behavior of these membranes was similar to that of the human skin. In all cases, the best fit for the permeation-lipophilicity correlation was provided by the bilinear model. It was demonstrated that this type of correlation, when a dimethylpolysiloxane membrane is used, is due to the existence of a supplementary stagnant aqueous layer adjacent to the membrane in the receptor compartment. This is clear from the fact that when Polysorbate 80 is added to the receptor solution, the effect of this layer is abolished. In these conditions, hyperbolic equation gives, consequently, the best fit for penetration-lipophilicity correlation. On the basis of the data obtained with rat skin and Polysorbate 80 in the receptor solution, it can be concluded that for biological membranes the bilinear model obtained is due to their heterogeneous nature. The optimum lipophilicity value for penetration according to the bilinear model was not the same for all the membranes assayed. Human and rat skin were qualitatively similar in behavior.

Monolayer systems-comparison: In designing effective therapeutic strategies, novel drugs must exhibit favorable Youdim et al. (2003)

pharmacokinetic properties. The physico-chemical characteristics of a drug, such as pKa, MW, solubility, and lipophilicity, will influence the way the drug partitions from the aqueous phase into membranes, and thus, will influence its ability to cross cellular barriers, such as the lining of the GIT and the BBB. Physico-chemical characteristics also influence the degree to which a drug is able to cross a barrier layer, and the route by which it does this; whether transcellular (across the cells)—by diffusion, carrier-mediated transport or transcytosis—or paracellular—by diffusing through the tight junctions between the cells. The in vitro model systems that are currently employed to screen the permeation characteristics of a drug often represent a compromise between HT with low predictive potential and low throughput with high predictive potential. Here, we will examine the way in which in vitro cellular permeability assays are often performed and the assumptions that are implied but sometimes forgotten, and we will make simple suggestions for improving the methodological techniques and mathematical equations used to determine drug permeability.

Multilayer membrane-permeability-cellulose lipid: The permeability properties of multilayer planar membranes of uniformly oriented lipids between a pair of cellulose sheets were investigated. The effect of the two cellulose sheets supporting the lipid membrane on the glucose or the Ca permeation was subtracted empirically, and values of 5 x 10(-6)and8 x 10(-6) cm/sec were thus obtained for the permeability coefficients of an egg yolk lecithin (egg PC)-cholesterol membrane of about 200 bilayers to Ca2+ and glucose, respectively. These values are discussed as compared with the permeability coefficients of other model membranes. The membrane permeability was moderately affected by the addition of chemical substances to egg PC membranes. It was reduced by the presence of cholesterol, but enhanced by the presence of isopropanol, n-butanol, or thymol in the same solution above a critical concentration of each compound. These and previous observations suggest that a close correlation may exist between the permeability of the membrane and the orientation of the membrane lipids. The glucose permeation was drastically suppressed by the presence of Ca2+ (10 mM) in the sample solution with the membrane containing phosphatidylserine, but was not at all suppressed with the membrane of the egg PC-cholesterol mixture.

PAMPA modified-BBB-HT: The recent advances in HTS for biological activities and combinatorial chemistry have greatly expanded the number of drug candidates. Rapid screening for BBB penetration potential early in drug discovery programs provides important information for compound selection and guidance of synthesis for desirable CNS properties. In this paper, we discuss a modification of the PAMPA for the prediction of BBB penetration (PAMPA-BBB). The assay was developed with 30 structurally diverse commercial drugs and validated with 14 Wyeth Research compounds. The PAMPA-BBB assay has the advantages of: predicting passive BBB penetration with high success, HT, low cost, and reproducibility.

PAMPA-biomimetic-Caco-2-comparison: Several in vitro assays have been developed to evaluate the Gl absorption of compounds. Our aim was to compare three of these methods: (/) the BAMPA method, which offers a HT, noncellular approach to the measurement of passive transport; (//) the traditional Caco-2 cell assay, the use of which as a HT tool is limited by the long cell differentiation time (21 days); and (//'/) The BioCoat HTS Caco-2 assay system, which reduces Caco-2 cell differentiation to three days. The transport of known compounds (such as cephalexin, propranolol, or chlorothiazide) was studied at pH 7.4 and 6.5 in BAMPA and both Caco-2 cell models. Permeability data obtained was correlated to known values of human absorption. Best correlations (r= 0.9) were obtained at pH 6.5 for BAMPA and at pH 7.4 for the Caco-2 cells grown for 21 days. The Caco-2 BioCoat HTS Caco-2 assay system does not seem to be adequate for the prediction of absorption. The overall results indicate that BAMPA and the 21-day Caco-2 system can be complementary for an accurate prediction of human intestinal absorption.

PAMPA-Caco-2-permeability-fluoroquinolones: PAMPA was used to measure the effective permeability, Pe, as a function of pH from 4 to 10, of 17 fluoroquinolones, including three congeneric series with systematically varied alkyl chain length at the 4'A/-position of the piperazine residue. The permeability values spanned over three orders of magnitude. The intrinsic permeability, Pc, and the membrane permeability, Pm, were determined from the pH dependence of the effective permeability. The pKa values were determined potentiometrically. The PAMPA method employed stirring, adjusted such that the unstirred water layer (UWL) thickness matched the estimated 30-100-|j,m range in the human small intestine. The intrinsic permeability coefficients [10(-6) cm/sec], representing the permeability of the uncharged form of the drug, are for 4'A/-/If-norfloxacin: 0.7 (R=H), 49 (Me), 132 (n-Pr), 365 (n-Bu); 4'/V-f?-ciprofloxacin: 2.7 (H), 37 (Me), 137 (n-Pr), 302 (n-Bu); A'N-R-3!-methylciprofloxacin: 3.8 (H), 20 (Me), 51 (Et), 160 (n-Pr), 418 (n-Bu). Increasing the alkyl chain length in the congeneric

Yamamoto et al. (1980)

Miretet al. (2004)

Bermejo et al. (2004)

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