Liquid phase

Figure 5.15 Diagram showing opportunities in plastic systems for adsorption of drug molecules, partitioning into and eventually permeation through the plastic. Leaching of molecules from the plastic also may occur.

5.10.3 A chromatographic model for the biophase

Octanol/water partition coefficients, as we have seen, have been useful predictors of biological activity. In spite of this it has been suggested that bulk liquid phases may not be the most appropriate models for a structured biophase such as a biological membrane, and chromato-graphic stationary phases have been proposed as an alternative because of the structuring of the 'membranous' hydrophobic chains.

PE1 being a 'proximity effect,' an adjusting fraction for polar fragments in nonpolar surroundings. So log


compared with a measured value of 1.34.

A method based on the surface areas of molecules has also been proposed to obtain measures of log P in a manner analogous to the calculation of solubility.19 Computer programs for calculation of log P are also in use and are described in detail, in Leo's 1993 review.15

5.1G.5 Drug distribution into human milk

5.10.4 Calculating log P from molecular structures

The large number of methods used to calculate log P values have been elegantly reviewed by Leo.15 The method proposed in 1964 by Fujita, Iwasa and Hansch17 used values for the 'parent' molecule and values for substituents gathered by analysis of thousands of values of log P for homologous and other series. In this method of 'substituents' log P is considered to be an additive-constitutive free-energy-related property, where one can define n for substituent X as the difference between the log P values for the parent solute and the compound with the substituent:

log P = 2.13 - 0.28 + 0.56 = 2.41 against a measured value of 2.45.

The distribution of drugs into the milk of breastfeeding mothers is of obvious importance. Nearly all drugs find their way into milk and it is, therefore, useful to be able to predict which of them will achieve high concentrations in milk in relation to their plasma level, defined in one model20 described below as the milk : plasma (M/P) ratio (see Table 5.21). Three key parameters are the pKa of the drug, plasma protein binding and the octanol/water partition coefficients of the drugs. Protein binding is the most important single predictor, an increase in M/P ratios generally being found as protein binding decreases.

The two key equations, each with three independent variables, are as follows:

For basic drugs:

Table 5.21

Distribution of drugs into milk: the M/P ratioa,b

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