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Time-dependent inhibition (TDI) of CYP3A is an important mechanism underlying numerous drug-drug interactions (DDIs), and assays to measure this are done to support early drug research efforts. However, measuring TDI of CYP3A in human liver microsomes (HLMs) frequently yields overestimations of clinical DDIs and thus can lead to the erroneous elimination of many viable drug candidates from further development. In this investigation, 50 drugs were evaluated for TDI in HLMs and suspended human hepatocytes (HHEPs) to define appropriate boundary lines for the TDI parameter rate constant for inhibition (k obs ) at a concentration of 30 µM. In HLMs, a k obs value of 0.002 minute -1 was statistically distinguishable from control; however, many drugs show k obs greater than this but do not cause DDI. A boundary line defined by the drug with the lowest k obs that causes a DDI (diltiazem) was established at 0.01 minute -1 Even with this boundary, of the 33 drugs above this value, only 61% cause a DDI (true positive rate). A corresponding analysis was done using HHEPs; k obs of 0.0015 minute -1 was statistically distinguishable from control, and the boundary was established at 0.006 minute -1 Values of k obs in HHEPs were almost always lower than those in HLMs. These findings offer a practical guide to the use of TDI data for CYP3A in early drug-discovery research. SIGNIFICANCE STATEMENT: Time-dependent inhibition of CYP3A is responsible for many drug interactions. In vitro assays are employed in early drug research to identify and remove CYP3A time-dependent inhibitors from further consideration. This analysis demonstrates suitable boundaries for inactivation rates to better delineate drug candidates for their potential to cause clinically significant drug interactions.

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Cytochrome P450 3A Time-Dependent Inhibition Assays Are Too Sensitive for Identification of Drugs Causing Clinically Significant Drug-Drug Interactions: A Comparison of Human Liver Microsomes and Hepatocytes and Definition of Boundaries for Inactivation Rate Constants