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P1001
CYP450 Inhibition Profiling Using High-Throughput RapidFire Mass Spectrometry Assays
Presenter Wentao Zhang, Exelixis, Inc., USA
Additional Authors: Sean Wu, Jing Wang, Lory Tan, Stefan Engst, and Kirk McMillan
Early assessment of ADME (Absorption, Distribution, Metabolism, and Excretion) properties of drug candidates has become an essential component of drug discovery. ADME characterizations are important in identifying compounds that are likely to fail in clinical development, meanwhile prioritizing candidates that are more likely to have good human pharmacokinetic properties and to avoid or minimize potential drug-drug interactions. At Exelixis we have established the capability to profile compounds (>100 compounds/week) in a panel of ADME assays in parallel with biochemical and cellular characterization.
Cytochrome P450 enzymes catalyze the biotransformation of the majority of xenobiotics in the liver and other tissues. The predominant drug metabolizing CYP450 isozymes are CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2C8. We have established LC-MS methods to assay these CYP450 isozymes expressed in human liver microsomes using specific drug substrates. Recently we integrated a RapidFire system with an ABI3000 mass spectrometer to increase throughput of these assays. This system has enabled a real-time and quantitative measurement of CYP450 inhibition in a dose-response manner, providing a rapid evaluation of potential clinically important drug-drug interactions. The assay development, process, and CYP450 results obtained with the RapidFire system will be presented.