Advertisement

When Enough Is Now Too Much

Fatal Forty DDI: midazolam, itraconazole, CYP3A4
  • Erica D. Wittwer
  • Juraj Sprung
  • Wayne T. Nicholson

Abstract

This case discusses the pharmacokinetic interaction between midazolam and itraconazole, resulting in increased sedation. Midazolam is a cytochrome P450 3A4 substrate and itraconazole is a 3A4 inhibitor.

Keywords

Pharmacokinetic Inhibition Inhibitor Midazolam Benzodiazepine Hydroxyitraconazole First-pass metabolism Cyclosporine Tacrolimus Alprazolam Triazolam Nifedipine Felodipine Simvastatin Lovastatin Vincristine sulfate Terfenadine Astemizole CYP 3A4 Cytochrome P450 

References

  1. 1.
    Quinney SK, Galinsky RE, Jiyamapa-Serna VA, et al. Hydroxyitraconazole, formed during intestinal first-pass metabolism of itraconazole, controls the time course of hepatic CYP3A inhibition and the bioavailability of itraconazole in rats. Drug Metab Dispos. 2008;36:1097–101.PubMedCrossRefGoogle Scholar
  2. 2.
    Isoherranen N, Kunze KL, Allen KE, et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos. 2004;32:1121–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55:481–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Ahonen J, Olkkola KT, Neuvonen PJ. Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers. Br J Clin Pharmacol. 1995;40:270–2.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg. 1996;82:511–6.PubMedGoogle Scholar
  6. 6.
    Krishna G, Moton A, Ma L, et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther. 2009;31:286–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38:111–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Erica D. Wittwer
    • 1
  • Juraj Sprung
    • 1
  • Wayne T. Nicholson
    • 1
  1. 1.Department of AnesthesiologyMayo ClinicRochesterUSA

Personalised recommendations