TY - JOUR T1 - CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1039 LP - 1046 DO - 10.1124/dmd.110.037911 VL - 39 IS - 6 AU - Alfred Zimmerlin AU - Markus Trunzer AU - Bernard Faller Y1 - 2011/06/01 UR - http://dmd.aspetjournals.org/content/39/6/1039.abstract N2 - Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (kinact and KI) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (kobs) at a single concentration of test compound (10 μM). The advantages of this new assay format are highlighted by comparison with data generated using the IC50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative kobs bin of 0.02 min−1, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling. ER -