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. Many of the concepts translate directly to the HTS context.
DeWitte
Robert S
RS
New Pharma R&D Solutions, Thermo Electron Corporation, 5344 John Lucas Drive, Burlington, Ontario L7L 6A6, Canada. robert.dewitte@thermo.com
D000818:Animals; D016477:Artifacts; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D010599:Pharmacokinetics; D012107:Research Design; D012995:Solubility; D018675:Toxicity Tests