substitute for two-lipid partition measurements, thus reducing the amount of measurement needed. Also, they introduced the use of polar surface areas as an interesting alternative to the use of A log P. Abraham et al. [257] analyzed the A log P parameter in terms of the Abraham descriptors to broaden the understanding of the concept. Von Geldern et al. [252] used the A log P parameter to optimize structural modifications to a series of endothelin A-receptor antagonists to improve gut absorption. A urea fragment in their series of molecules had NH residues systematically replaced with NCH3, O, and CH2, and correlations between A log P and antagonist selectivity effectively guided the optimization procedure.

Avdeef et al. [556] measured the PAMPA permeabilities of a series of drug molecules and natural products using both dodecane- and (dodecane + 2%DOPC)-coated filters. It was proposed that a new H-bonding scale could be explored, based not on partition coefficients but on permeabilities.

Figure 7.50 shows A log Pe (difference permeability) versus log Pe (dodecane-treated filters) for a series of common drugs and research compounds at pH 7.4. Some of the differences are positive, and some are negative. For example, phena-zopyridine is attenuated by the presence of DOPC in the dodecane, but diltiazem is accelerated by the DOPC [556]. The effects are most pronounced where the permeability in pure dodecane is less than about 3 x 10-6cm/s. That is, molecules that are very permeable in dodecane are unaffected by the presence of DOPC, as

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