A hierarchical screening methodology for physicochemical/ADME/Tox profiling.

Full integration of pharmaceutical profiling into pharmaceutical lead selection and optimisation requires that complete sets of unequivocal data be available at the time compound design or advancement decisions are made. As the productivity of chemical synthesis expands, and the breadth of profiling assays grow in scope, physicochemical/ADME/Tox laboratories are being challenged to produce ever more data to support an accelerating decision cycle. This article focuses on the challenges of increasing preclinical profiling productivity while managing lower accuracy higher throughput data streams to preserve confidence in decision making.

Avoiding physicochemical artefacts in early ADME-Tox experiments.

Recent literature has highlighted the importance of fundamental physicochemical properties in HTS and ADME-Tox: high lipophilicity, low dimethyl sulfoxide solubility, low aqueous solubility, aggregation and nonspecific binding to proteins and phospholipids. Unless carefully controlled for, each of these artefacts can confound individual ADME-Tox results and their interpretation on aggregate. This article reviews the impact of these phenomena and suggests experimental strategies for minimizing the magnitude and frequency of these artefacts without compromising the essential speed of the experimental process.