In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A

Thomas Polasek, Janani Sadagopal, David Elliot, John Miners

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    Abstract

    Objectives To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitroin vivo extrapolation; IV-IVE). Methods A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (KI and kinact) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam. Results Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following preincubation. In HLMs, the concentration required for half maximal inactivation (KI) was 122 μM and the maximal rate of inactivation (kinact) was 0.094 min-1. In comparison, KI and kinact values with rCYP3A4 were 50 μM and 0.229 min-1, respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively.Conclusions Zolpidem is a relatively weak mechanismbased inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.

    Original languageEnglish
    Pages (from-to)275-283
    Number of pages9
    JournalEuropean Journal of Clinical Pharmacology
    Volume66
    Issue number3
    DOIs
    Publication statusPublished - Mar 2010

    Keywords

    • CYP3A
    • Cytochromes P450
    • Drug-drug interactions
    • In vitro-in vivo extrapolation
    • Mechanism-based inactivation
    • Midazolam
    • Modelling and simulation
    • Zolpidem

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