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October 21, 2004, 1st Annual PhysChem Symposium: Early ADME and Medicinal Chemistry
The Role of Lipophilicity and Acid/Base Character in Drug Disposition "in vivo"
Kláara Valkó, Shenaz Nunhuck, Ferenc Hollósy & Chris Bevan (GlaxoSmithKline)
Abstract
Numerous publications demonstrate the relationship between lipophilicity and various "developability" parameters, such as permeability, solubility, oral absorption, bioavailability, CNS penetration, metabolism, etc. The lipophilicity of a compound is usually assigned based on its octanol/water partition coefficient. Ionisation affects lipophilicity and produces change over several orders of magnitude. The HPLC technique has a great potential to determine compound distribution properties through retention time measurements. Various stationary phases can be used, such as C-18, octanol, immobilised artificial membrane (IAM), human serum albumin (HSA), alpha-acid glycoprotein (AGP), etc. The mobile phase pH can be altered for the investigation of the effect of charge and to obtain a quantitative measure of acid/base character. The dynamic range can be increased by applying a fast gradient to alter the mobile phase polarity and thus decrease the analysis time without decreasing precision. More than 100,000 HPLC based lipophilicity measurements have been made in our laboratories to support more than 70 projects in the lead optimisation stage. The analysis of these data revealed that they have enough precision to build general and project specific models for estimating biopharmaceutical properties. We shall present a model for the in vivo volume of distribution of known drug molecules that is based on the difference between the IAM partition and serum albumin binding. A good correlation between the chromatographic lipophilicity (CHIlogP) and the intrinsic permeability will also be presented. The analyses have also revealed significant discrepancies with calculated property data, thus providing the opportunity to derive improved in silico models. Examples will be shown for the effect of positive and negative charges on the biomimetic partitions (HSA binding, IAM partition) that proved to be very different from the effect of charge on the octanol/water partition.
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