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 vitro-in 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 (K I and k inact) 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 pre-incubation. In HLMs, the concentration required for half maximal inactivation (K I) was 122 µM and the maximal rate of inactivation (k inact) was 0.094 min−1. In comparison, K I and k inact 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 mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.
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Acknowledgements
This work was supported by grants from the Flinders Medical Centre Foundation and the National Health and Medical Research Council of Australia. We thank Benjamin C. Lewis for the preparation of recombinant CYP3A4 and Kushari Bowalgaha for assisting in the preparation of human liver microsomes. The authors declare that experiments with human liver tissue were approved by the Flinders Medical Centre Ethics Review Committee under current Australian Law. Part of this work was presented at the 16th North American ISSX meeting, October 2009, Baltimore, MD, USA.
The authors have no competing interests to declare.
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Polasek, T.M., Sadagopal, J.S., Elliot, D.J. et al. In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A. Eur J Clin Pharmacol 66, 275–283 (2010). https://doi.org/10.1007/s00228-009-0760-2
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DOI: https://doi.org/10.1007/s00228-009-0760-2