Various CYP time-dependent inhibition (TDI) assays have been widely implemented in drug discovery and development
which has led to great success in positively identifying compounds with mechanism-base inhibition liability.
However, drug-drug interaction (DDI) predictions by various in-silico models utilizing kinetic parameters obtained from
TDI assays have met with significant challenges including questionable kinetic data, over-simplified in-vitro models and
unreliable mathematic algorithms. Although significant efforts have been made to standardize the TDI assay and refine
mathematical models, recent evaluation studies have revealed that the kinetic parameters of TDI, the most important invitro
data required by all DDI prediction models, are significantly impacted by a variety of experimental variables including
microsomal protein concentration, metabolic stability, CYP-specific probes, and post-incubation time. This review attempts
to provide medicinal chemists a brief overview on the current status of TDI assays, determination of kinetic parameters
and in silico DDI predictions with emphasis on the complexity of the TDI kinetics and limitations of current invitro
models and DDI prediction methodologies.
Keywords: Time-dependent CYP inhibition, drug-drug interactions, time-dependent inhibition (TDI) assays, drug-drug interaction (DDI), metabolic stability, CYP-specific probes, fluorescent substrate, LC/MS analysis, MBI assay
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