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Practical Aspects: The Conduct of TDI Experiments• These abbreviated methods can be used to identifythose compounds requiring determination of K I andk inact• If changes of 20-25% or less are observed in 30 minwith pooled HLM, then the compound is notconsidered a concern for DDI caused by TDI22
Practical Aspects: The Conduct of TDI Experiments• IC 50shift experiment:Another abbreviatedexperimental design toidentify TDI• Run as a typical IC 50experiment in the ‘control’state• Compared to an IC 50determined after the testcompound has beenpreincubated with enzymeand NADPH for 30 min• If IC 50difference is 1.5X ormore, the compound is aninactivator% of control activity10075502500.01 0.1 1 10 100[inactivator] (uM)inactivation incubation without NADPHinactivation incubation with NADPH23
Page 3 and 4: IntroductionFrom Appendix C-2 of th
Page 5 and 6: Time-Dependent Inhibition of P450En
Page 15 and 16: Practical Aspects: The Conduct of T
Page 21: Practical Aspects: The Conduct of T
Page 25 and 26: Practical Aspects: Predicting DDI f
Page 27 and 28: Practical Aspects: Predicting DDI f
Page 29 and 30: Summary of the PhRMA Survey of TDI
Page 39 and 40: TDI and DDI Decision TreeNME is tes
Page 41: White Paper CoauthorsHeidi Einolf,

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