This method utilized the PSR4p instrument from pIon, Inc. Permeability is determined by passive diffusion of a substance through an artificial membrane coated with lipid. Experiments were performed to determine the permeability of compounds at pH 7.4 in both acceptor and donor compartments. The same compounds were then tested using conditions in which the acceptor compartment was held at pH 7.4, while the pH of the donor well was varied as 5.0, 6.2, and 7.4. The sample set consisted of acidic, basic and neutral compounds.
Both methods produced good interday and intraday precision. The iso-pH method produced some false negative results for weak acids as a result of the compounds being charged at pH 7.4. The multiple-pH gradient method showed the pH dependence of permeability measurements.
Each method has a place in the drug discovery setting. For early screening in the very high throughput mode, the iso-pH measurement offers a good first estimation of compound permeability by passive diffusion in a timely manner. For lead series and later discovery compounds a multiple-pH approach can give a broader understanding of the compound permeability at different pH that mimic their passage through the intestinal tract.
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