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The General Solubility Equation (GSE) is a QSPR model based on the melting point and log P of a chemical substance. It is used to predict the aqueous solubility of nonionizable chemical compounds. However, its reliance on experimentally derived descriptors, particularly melting point, limits its applicability to virtual compounds. The studies presented show that the GSE is able to predict, to within 1 log unit, the experimental aqueous solubility (log S) for 81% of the compounds in a data set of 1265 diverse chemical structures (-8.48 < log S < 1.58). However, the predictive ability of the GSE is reduced to 75% when applied to a subset of the data (1160 compounds -6.00 < log S < 0.00), which discounts those compounds occupying the sparsely populated regions of data space. This highlights how sparsely populated extremities of data sets can significantly skew results for linear regression-based models. Replacing the melting point descriptor of the GSE with a descriptor which accounts for topographical polar surface area (TPSA) produces a model of comparable quality to the GSE (the solubility of 81% of compounds in the full data set predicted accurately). As such, we propose an alternative simple model for predicting aqueous solubility which replaces the melting point descriptor of the GSE with TPSA and hence can be applied to virtual compounds. In addition, incorporating TPSA into the GSE in addition to log P and melting point gives a three descriptor model that improves accurate prediction of aqueous solubility over the GSE by 5.1% for the full and 6.6% for the reduced data set, respectively.

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1. The metabolic fates of the naturally occurring food flavours trans-anethole and estragole, and their synthetic congener p-propylanisole, have been investigated in human volunteers using the [methoxy-14C]-labelled compounds. The doses used were close to those encountered in the diet, 1 mg, 100 micrograms and 100 micrograms respectively. 2. In each case, the major routes of elimination of 14C were in the urine and in the expired air as 14CO2. 3. Urinary metabolites were separated by solvent extraction, t.l.c. and h.p.l.c., and characterized by comparison of chromatographic mobilities with standards and by radioisotope dilution. Nine 14C urinary metabolites were found after trans-anethole administration, four after p-propylanisole and five after estragole. All were products of side chain oxidations. 4. The principal metabolites of p-propylanisole were 4-methoxyhippuric acid (12%) and 1-(4'-methoxyphenyl)propan-1-ol (2%) and -2-ol (8%). 5. The major metabolite of trans-anethole was 4-methoxyhippuric acid (56% of dose), accompanied by much smaller amounts of the two isomers of 1-(4'-methoxyphenyl)propane-1,2-diol (together 3%). 6. After estragole administration, the two volunteers eliminated 0.2 and 0.4% of the dose respectively as 1'-hydroxyestragole. 7. The human metabolic data is discussed with reference to the comparative metabolic disposition of these compounds in the mouse and rat, species commonly used in their safety assessment.