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Probe of CYP3A by a single-point blood measurement after oral administration of midazolam in healthy elderly volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Midazolam (MDZ) is used as an assessment of human cytochrome P450 3A (CYP3A) activity. A single blood measurement is used as a marker of its activity based on an observed correlation between MDZ clearance and the 1′-hydroxymidazolam (1′-OH-MDZ): MDZ plasma ratio is assessed at 0.5 h followig the intake of a single 7.5 mg oral dose of MDZ in healthy young volunteers. In addition, a 4-h plasma MDZ measurement has been found to be an excellent predictor of AUC and CYP3A activity.

Objectives

The main aim of this study was to define a single-point blood sampling in healthy elderly volunteers. The secondary objective was to investigate the pharmacological effects of a low oral dose of MDZ (5 mg) and its potential psychometric changes.

Methods

Eight healthy elderly Caucasian volunteers participated in a single-dose, open-label, non-comparative study. Each subject received a single 5 mg oral dose of MDZ. Plasma concentrations of MDZ and its major metabolite, 1′-OH-MDZ, were assayed over 12 h. Secondary assessments of critical flicker fusion (CFF), body sway and mini-mental state examination were also carried out during the 12-h post-administration period.

Results

A moderate correlation was observed between MDZ clearance and the 1′-OH-MDZ: MDZ plasma concentration ratio at 9 h post-dosing (Rho=0.81; p=0.04), but an even better correlation (Rho=0.99; p<0.009) was found between MDZ AUC and MDZ plasma concentration at 6 h post-dosing, with the latter value corresponding approximately to the average mean residence time (MRT) determined in our trial. This study was well-tolerated despite a significant transitory decrease (relative to baseline) in cortical arousal at 1 h post-dosing, as assessed by CFF, and a non-significant decrease (relative to baseline) in balance and vigilance also measured at 1 h and assessed on body sway, compared to baseline values.

Conclusion

Despite the small sample size, based on the results of healthy, elderly volunteers, a single MDZ plasma measurement taken at 6 h post-oral administration may represent an accurate marker of CYP3A phenotype. This single-time-point method could be used safely for predicting drug-drug or diet interactions and identifying individuals with genetic polymorphism that affect CYP3A activity.

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Acknowledgements

This study was supported by the Délégation Régionale de la Recherche Clinique de la Région Poitou-Charentes, and conducted at the Clinical Research Center of Poitiers’ University Hospital, France. We thank Ms. Stephanie Ragot for her help in performing statistical analysis of demographic and pharmacodynamic data.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University Hospital, 2 rue de la Miletrie, 86021, Poitiers, France

    Emmanuel Krupka, Claire Lafay, David Gendre & Marie-Christine Perault

  2. Clinical Research Center, University Hospital, 2 rue de la Miletrie, Poitiers, France

    Emmanuel Krupka, David Gendre & Marie-Christine Perault

  3. Pharmacokinetic laboratory, University Hospital, Pôle de Biologie Santé, 2 rue de la Miletrie, Poitiers, France

    Nicolas Venisse & Serge Bouquet

  4. Department of Pharmacology and Toxicology, University Hospital, 4 rue Larrey, 49033, Angers, Cedex 09, France

    Bertrand Diquet

Authors
  1. Emmanuel Krupka
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  2. Nicolas Venisse
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  3. Claire Lafay
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  4. David Gendre
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  5. Bertrand Diquet
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  6. Serge Bouquet
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  7. Marie-Christine Perault
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Corresponding author

Correspondence to Marie-Christine Perault.

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In memoriam: S. Bouquet

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Krupka, E., Venisse, N., Lafay, C. et al. Probe of CYP3A by a single-point blood measurement after oral administration of midazolam in healthy elderly volunteers. Eur J Clin Pharmacol 62, 653–659 (2006). https://doi.org/10.1007/s00228-006-0159-2

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  • DOI: https://doi.org/10.1007/s00228-006-0159-2

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