Solubility structure-permeability relationship

Despite the availability of other cell lines, Caco-2 cells remain the most widely used intestinal cell culture model at present. This model has provided valuable information necessary for lead optimization in the drug discovery process. However, it is important to understand that compounds with high permeability in this model are typically well absorbed, whereas compounds with low solubility and low permeability in this model may not necessarily be poorly absorbed in vivo. Although this type of positive selection limits the usefulness in providing a structure-permeability relationship, the Caco-2 model has the most effect in drug discovery when the screen is implemented early and in conjunction with other types of in vitro and in vivo permeability/absorption screens. 

Seelig A, Landwojtowicz E, Fischer H, Blatter XL. Towards P-glycoprotein structure-activity relationships. In van de Waterbeemd H, Lennernas H, and Artursson P. Drug bioavailability — Estimation of solubility, permeability, absorption and bioavailability. Methods and Principles of Medicinal Chemistry, vol 18. Weinheim Wiley-VCH Verlag GmbH Co 2003. Chap 20, p. 461-92. 

The relationship between chemical structure, lipophilicity, and its disposition in vivo has been extensively studied. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance. Activities used in quantitative structure-activity relationships (QSAR) include chemical measurements and biological assays. QSAR currently are applied in many disciplines, with many pertaining to drug design and environmental risk assessment. 

We will deal with the permeability in greatest detail, because it is the quantity of most direct interest in applications. In developing a more fundamental theoretical understanding of transport, however, it will be crucial to consider the diffusivity and the solubility separately. Many of the shortcomings of simple structure-property relationships for the permeability and selectivity may possibly be overcome by a more fundamental understanding, which may therefore also be useful in future refinements and practical applications of correlative schemes. 

Note that the most powerful method of improving solubility, adding in carboxylic acids or amines in order to form soluble salts, should have quite an adverse effect on permeability, unless it reduces overall charge as for lisinopril or coincidentally produces a substrate for carrier-mediated transport (e.g. via an amino acid or dipeptide transporter). In short, structure property relationships for solubility and cell permeability, like many properties that need to be optimized in going from a hit to a clinical candidate, operate by different rules, and often go in opposite directions. 

Polymer structure and its property relationships governing gas transport of PPO and modified PPO was therefore well described by Story and Koros. They explained the differences in permeability and permeability ratio for CO2/CH4 of the modified polymers in terms of the effect of the substituent groups on the solubility and the diffusivity factors. Solubility selectivity of PPO was improved by substituting the methyl side chain site of the PPO backbone with carboxyl or methyl esterified carboxyl groups. The increase in solubility selectivity was attributed to the enhanced chemical interactions... 

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