Cd

su series resulted in increased permeability, averaging about 0.34 log units per methylene group, except that of the first (H-to-Me), which was about 1.2 log units. These results were compared with Caco-2 and rat in situ permeability measurements. The in situ closed loop technique used for obtaining permeability values in rat showed a water layer thickness effect quite consistent with in vivo expectations. The rat-PAMPA correlation (r2 = 0.87) was better than that of rat-Caco-2 (r2 = 0.63). Caco-2-PAMPA correlation indicated that r2 = 0.66. The latter correlation improved significantly (r2 = 0.82) when the Caco-2 data were corrected for the UWL effect.

PAMPA-Caco-2-log D, log P-PSA-correlation: Artificial membrane permeability measurement is a potentially HT and low-cost alternative for in vitro assessment of drug absorption potential. It will be an ideal screening/profiling tool in the lead generation program of drug discovery research if it is proven to be generally applicable for classifying drug absorption potential and is advantageous over other in vitro or in silico methods. This study provides an in-depth evaluation of the method in close comparison with Caco-2, log D, log P, PSA, and QSPR predictions using a large and diverse compound set. It showed that the accuracy of using artificial membrane permeability in assessing drug absorption is comparable with Caco-2, but significantly better than log P, log D, PSA, and QSPR predictions. This study also explored the artificial membrane composition by adopting a hydrophilic filter membrane for artificial membrane (lecithin-dodecane) support. The use of hydrophilic filter membrane increased the rate of permeation significantly and reduced the transport time to two hours or less as compared with over 10 hr when a hydrophobic filter membrane is used.

PAMPA-Caco-2-permeability-double sink: The aim of this study was to analyze pH-dependent permeability of cationic drugs in Caco-2 cell monolayers using the pKanux method and to correlate the results with those obtained in PAMPA. The pH-dependent permeability of verapamil and propranolol was studied in Caco-2 cell monolayers. The data were subsequently processed using software developed for the PAMPA pKa fiUx method. Literature values for an additional nine cationic drugs were also analyzed. Double-sink PAMPA data were also obtained for the same cationic drugs, to compare with the Caco-2 data. The Algorithm Builder program was then used to develop a predictive model of Caco-2 permeability based on PAMPA permeability and calculated Abraham molecular descriptors. From the relationship between permeability and pH, it was shown that in PAMPA, only the uncharged form of the drugs permeated across the membrane barrier, while charged and ionized forms of the drugs were significantly permeable in Caco-2. The charged form of permeability, Pu was therefore determined and subsequently subtracted from all permeability coefficients in Caco-2 prior to the comparison with PAMPA. The resulting intrinsic permeability coefficients (Pc) obtained in Caco-2 were successfully related to those derived from the PAMPA model. In this study, we have shown that permeability coefficients obtained in PAMPA can predict the passive transcellular permeability in Caco-2.

PAMPA-HT-oral absorption: Modified composition of lipid solution was used to make a lipid membrane on the filter support. First, they changed the chain length of organic solvent [PC/alkyldienes (C7-C10)]. A negative charge was then added to the membrane to mimic the intestinal membrane (PC/stearic acid/1,7-octadiene and PC/PE/PS/PI/cholesterol/1,7-octadiene). Finally, they examined the predictability of the PC/PE/PS/PI/CHO/1,7-octadiene membrane using structurally diverse compounds. Permeability coefficients of tested compounds were increased as the chain length of alkyldiene became shorter.

Avdeef et al. (2005)

Sugano et al. (2001)

The addition of a negative charge to the membrane increased the permeability of the basic compounds. However, the negatively charged membrane with stearic acid showed different permeability profiles from PC/PE/PS/PI/CHO. The predictability of the PC/PE/PS/PI/CHO/1,7-octadiene membrane was adequate (r= 0.858, n = 31) for use during the early stages of the drug discovery/development process.

PAMPA-hydrophilic basic compound (HBC): The permeation characteristics of a HBC in a bio-mimetic PAMPA were investigated. The bio-mimetic PAMPA membrane was constructed on a hydrophobic filter by impregnating a lipid solution consisting of phosphatidylcholine (0.8%, w/w), phosphatidylethanolamine (0.8%, w/w), phosphatidylserine (0.2%, w/w), phosphatidylinositol (0.2%, w/w), cholesterol (1.0%, w/w), and 1,7-octadiene (97.0%, w/w). The pH-permeability curve (pH 3-10), the effect of lipid composition, concentration dependency (0.02-2.00 mM), and inhibition by other cationic compounds, were investigated for several HBCs. Ketoprofen and methylchlorpromazine were also employed as an acidic and a quaternary ammonium compound, respectively. At pH 3-6, the permeability of timolol, a HBC, was higher than expected from the pH-partition hypothesis, especially in the Pl-containing membrane, whereas the pH-permeability curve of ketoprofen followed the pH-partition hypothesis. Permeation of HBC was saturable and inhibited by basic and quaternary ammonium compounds. Similar results were also found for methylchlorpromazine. The permeation characteristics of HBC observed in the present study are not usually expected in a passive permeation process across an artificial membrane. The participation of facilitated permeation of cationic species was suggested, in addition to a simple passive diffusion of un-dissociated species. Ion pair transport was suggested as a possible permeation mechanism of cationic species. However, further investigation is necessary to clarify the reason for the permeation characteristics of HBC.

PAMPA-LC/MS: The analytical techniques typically used for PAMPA sample analysis are HPLC-UV, LC/MS or more recently, the UV-plate reader. The LC techniques, though sturdy and accurate, are often labor- and time-intensive and are not ideal for HT. On the other hand, UV-plate reader technique is amenable to HT, but is not sensitive enough to detect the lower concentrations that are often encountered in early drug discovery work. This article investigates a novel analytical method, a chip-based automated nanoelectrospray mass spectrometry method for its ability to rapidly analyze PAMPA permeability samples. The utility and advantages of this novel analytical method is demonstrated by comparing PAMPA permeability values obtained from nanoelectrospray with those from conventional analytical methods. Ten marketed drugs having a broad range of structural space, physico-chemical properties, and extensive intestinal absorption were selected as test compounds for this investigation. PAMPA permeability and recovery experiments were conducted with model compounds followed by analysis by UV-plate reader, UV-HPLC, and the automated nanoelectrospray technique (nanoESI-MS/MS). There was a very good correlation (r2 > 0.9) between the results obtained using nanoelectrospray and the other analytical techniques tested. Moreover, the nanoelectrospray approach presented several advantages over the standard techniques, such as higher sensitivity and ability to detect individual compounds in cassette studies, making it an attractive HT analytical technique. Thus, it has been demonstrated that nanoelectrospray analysis provides a highly efficient and accurate analytical methodology to analyze.

Sugano et al. (2004)

Balimane et al. (2005)

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