IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4

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    The predictive utility of two in vitro methods (empirical IC50-based and mechanistic kinact/KI) for the assessment of time-dependent cytochrome P450 3A4 (CYP3A4) inhibition has been compared. IC50 values were determined at multiple pre-incubation time points over 30min for five CYP3A4 time-dependent inhibitors (verapamil, diltiazem, erythromycin, clarithromycin, and azithromycin). The ability of IC50 data obtained following pre-incubation to predict kinact/KI parameters was investigated and its utility was assessed relative to the conventional kinact/KI model using 50 reported clinical drugdrug interactions (DDIs). Models with either hepatic or hepatic with intestinal components were explored. For low/medium potency time-dependent inhibitors, 81% of the predicted kinact/KI(unbound) from IC50 data were within an order of magnitude of the actual values, in contrast to >50% of potent inhibitors. An underprediction trend and >50% of false-negatives were observed when IC50 data were used in the DDI hepatic prediction model; incorporation of the intestine improved the prediction accuracy. On the contrary, 86% of the DDI studies were predicted within twofold using kinact/KI mechanistic approach and the combined hepatic and intestinal model. Use of the empirical IC50 approach as an alternative to the mechanistic kinact/KI model for in vivo DDI prediction is limited and is best restricted to preliminary investigations.
    Original languageEnglish
    Pages (from-to)331-343
    Number of pages12
    Issue number5
    Publication statusPublished - May 2010


    • CYP3A4
    • Drug-drug interactions
    • Time-dependent inhibition


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