European Journal of Clinical Pharmacology

, Volume 59, Issue 8–9, pp 615–619 | Cite as

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers

  • Manami Oda
  • Tsutomu Kotegawa
  • Kimiko Tsutsumi
  • Yasukiyo Ohtani
  • Keiji Kuwatani
  • Shigeyuki Nakano
Pharmacokinetics and Disposition


Rationale and objective

Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P 450 (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam.


Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration.


Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (±SD) values of area under the plasma concentration–time curve and elimination half-life for placebo versus itraconazole were 1328±330 ng h/ml versus 1445±419 ng h/ml and 32.1±9.3 h versus 31.1±8.4 h, respectively.


The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors.


Bromazepam Itraconazole CYP3A4 



Supported in part by Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (no.13672393)


  1. 1.
    Schwartz MA, Postma E, Kolis SJ, Leon AS (1973) Metabolites of bromazepam, a benzodiazepine, in the human, dog, rat, and mouse. J Pharm Sci 62:1776–1779PubMedGoogle Scholar
  2. 2.
    Kaplan SA, Jack ML, Weinfeld RE, Glover W, Weissman L, Cotler S (1976) Biopharmaceutical and clinical pharmacokinetic profile of bromazepam. J Pharmacokinet Biopharm 4:1–16PubMedGoogle Scholar
  3. 3.
    Ochs HR, Greenblatt DJ, Friedman H, Burstein ES, Locniskar A, Harmatz JS, Shader RI (1987) Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol. Clin Pharmacol Ther 41:562–570PubMedGoogle Scholar
  4. 4.
    van Harten J, Holland RL, Wesnes K (1992) Influence of multiple-dose administration of fluvoxamine on the pharmacokinetics of the benzodiazepines bromazepam and lorazepam: a randomized, cross-over study. Eur Neuropsychopharmacol 2:381PCrossRefGoogle Scholar
  5. 5.
    Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S (2002) Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method. J Clin Pharmacol 42:183–191CrossRefPubMedGoogle Scholar
  6. 6.
    Hargreaves JA, Jezequel S, Houston JB (1994) Effect of azole antifungals on human microsomal metabolism of diclofenac and midazolam. Br J Clin Pharmacol 38:175PGoogle Scholar
  7. 7.
    Collignon P, Hurley B, Mitchell D (1989) Interaction of fluconazole with cyclosporin. Lancet 1:1262PGoogle Scholar
  8. 8.
    Torregrosa V, de la Torre M, Campistol JM, Oppenheimer F, Ricart MJ, Vilardell J, Andreu J (1992) Interaction of fluconazole with cyclosporin A. Nephron 60:125–126PubMedGoogle Scholar
  9. 9.
    Krüger HU, Schuler U, Zimmermann R, Ehninger G (1989) Absence of significant interaction of fluconazole with cyclosporin. J Antimicrob Chemother 24:781–786PubMedGoogle Scholar
  10. 10.
    Lazar JD, Wilner KD (1990) Drug interactions with fluconazole. Rev Infect Dis 12:S327–S333PubMedGoogle Scholar
  11. 11.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 38:111–180Google Scholar
  12. 12.
    Bailey DG, Malcolm J, Arnold O, Spence JD (1998) Grapefruit juice–drug interactions. Br J Clin Pharmacol 46:101–110PubMedGoogle Scholar
  13. 13.
    Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002) St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 54:349–356CrossRefPubMedGoogle Scholar
  14. 14.
    Olkkola KT, Backman JT, Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481–485PubMedGoogle Scholar
  15. 15.
    Varhe A, Olkkola KT, Neuvonen PJ (1994) Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56:601–607Google Scholar
  16. 16.
    Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K (1998) Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology 139:269–273Google Scholar
  17. 17.
    Kwan JTC, Foxall PJD, Davidson DGC, Bending MR, Eisinger AJ (1987) Interaction of cyclosporine and itraconazole. Lancet 2:282Google Scholar
  18. 18.
    Trenk D, Brett W, Jähnchen E, Birnbaum D (1987) Time course of cyclosporine/itraconazole interaction. Lancet 2:1335–1336CrossRefGoogle Scholar
  19. 19.
    Neuvonen PJ, Kantola T, Kivistö KT (1998) Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 63:332–341Google Scholar
  20. 20.
    Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP (1991) Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology 101:1680–1691PubMedGoogle Scholar
  21. 21.
    Caccia S (1998) Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 34:281–302Google Scholar
  22. 22.
    Preskorn SH (1997) Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 32[Suppl1]:1–21Google Scholar
  23. 23.
    Kyriakopoulos AA, Greenblatt DJ, Shader RI (1978) Clinical pharmacokinetics of lorazepam: a review. J Clin Psychiatry 39:16–23PubMedGoogle Scholar
  24. 24.
    Patwardhan RV, Yarborough GW, Desmond PV, Johnson RF, Schenker S Jr, Speeg KV (1980) Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 79:912–916PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Manami Oda
    • 1
  • Tsutomu Kotegawa
    • 2
  • Kimiko Tsutsumi
    • 1
  • Yasukiyo Ohtani
    • 2
  • Keiji Kuwatani
    • 1
  • Shigeyuki Nakano
    • 1
    • 2
  1. 1.Department of Clinical Pharmacology and TherapeuticsOita Medical UniversityOitaJapan
  2. 2.Clinical Pharmacology CenterOita Medical University HospitalOitaJapan

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