Physicochemistry and the Off-Target Effects of Drug Molecules

Measurement of log P and log D can be automated, but there are many in silico methods available. Every fragment of an organic compound has a defined lipophilicity. Calculation of log P can be made computationally by summing the fragments to give a total lipophilicity (Leo etal., 1971 Rekker andMannhold, 1992) A variety of methods 

Drug Discovery Toxicology From Target Assessment to Translational Biomarkers, First Edition. Edited by Yvonne Will, J. Eric McDuffie, Andrew J. Olaharski, and Brandon D. Jeffy. 

Calculation of is also routinely achieved by computational methods with several programs giving relatively low variance from measured values and identifying the site of ionization correctly (Shields and Seybold, 2013). 

One limitation of octanol as a solvent is the hydroxyl group and in addition its relatively high (4%) aqueous content (Smith et al 2012). Thus octanol supports hydrogen bonding and by itself will not completely characterize the behavior of a molecule. Alternative portioning systems such as cyclohexane are experimentally difficult, so the characterization of hydrogen bonding is normally carried out by simple calculations. 

Lipoidal or lipid permeability has been used to define the disposition characteristics of molecules (Wu and Benet, 2005). This permeability can be related to physicochemical properties as outlined earlier. The relationship can be extended to also the likely interaction sites for a molecule. Small, nonlipophilic molecules will rely on the paracellular pathway. Such molecules will be absorbed from the 

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