Cellular models for ADMET predictions and evaluation of drug-drug interactions.
Deficiencies in ADMET (absorption, distribution, metabolism, excretion and toxicity) properties and drug-drug interactions are collectively the major causes of attrition during drug development. As such, assays have been developed with which to study and optimize these key properties in early dug discovery. While screening using systems expressing discrete proteins have provided valuable insight, quantitative structure-activity relationships (QSARs) and predictive computational models, the ability to study several processes in tandem is paramount to in vivo projection. In particular, the key role of transporter proteins in controlling access to drug metabolizing enzymes and other intracellular processes cannot be overlooked. In this respect, cellular models provide a key platform to study the complex interplay between xenobiotic transport and metabolism, which underlie many ADMET issues. In addition, uptake and accumulation in tissues may provide a mechanistic insight into false negatives arising from simple, primary screens, for example, cytochrome P450 (CYP) inhibition analysis. Qualitative and quantitative interspecies differences in the regulation, expression and functional activity of key ADMET processes confound extrapolation from animals to man. However, complementary screens using animal and human material may assist the interpretation of safety assessment findings and help project the risk for early human studies.
AstraZeneca R&D Charnwood, Department of Physical and Metabolic Science, Loughborough, Leicestershire LE11 5RH, UK. rob.riley@astrazeneca.com
Robert J
RJ
Riley
J Gerry
JG
Kenna
D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
D004364:Pharmaceutical Preparations