pH 7.4 (Acceptor)

3456789 10 pH (Donor)

Figure 7.48 Negatively charged PAMPA models showing no evidence for violation of the pH partition hypothesis.

Seiler [250] proposed a way of estimating the extent of hydrogen bonding in solute partitioning between water and a lipid phase by measuring the so-called A log P parameter. The latter parameter is usually defined as the difference between the partition coefficient of a solute measured in the octanol-water system and that measured in an inert alkane-water suspension: A log P = log Kp oct — log Kp alk.

Young et al. [599] demonstrated the usefulness of the A log P parameter in the prediction of brain penetration of a series of H2-receptor histamine antagonists. Neither log Kp oct nor log Kp alk was found to correlate with brain penetration, log BB (where BB is defined as the ratio of the compound concentration in the brain and the compound concentration in plasma). However, the difference between the two partition coefficients correlated well, as shown in Fig. 7.49. When the difference is large, so is the H bonding expressed by the solute, and less brain penetration is expected. It was suggested that the A log P parameter accounts for H-bonding ability and reflects two distinct processes—alkane encodes the partitioning into nonpolar regions of the brain and octanol encodes protein binding in the peripheral blood. El Tayar et al. [255] elaborated that the parameter contains information on the capacity of a solute to donate H bonds; the rate-limiting step in brain penetration was proposed to be the donation of H bonds of solute to hydrophilic parts of lipids in the blood-brain barrier (BBB). Van de Waterbeemd and Kansy [251] reexamined Young et al. [599] data with solvatochromic equations for identifying physicochemical properties governing solubility and partitioning. They suggested that the combination of calculated molar volumes and just the log log Kpalk could

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