Skip to main content
SpringerLink
Log in

Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam

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

Abstract

Objective:

Grapefruit juice (GFJ) inhibits cytochrome P450 (CYP) 3A4 in the gut wall and increases blood concentrations of CYP3A4 substrates by the enhancement of oral bioavailability. The effects of GFJ on two benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C9), were determined in this study.

Methods:

The study consisted of four separate trials in which nine healthy subjects were administered 0.25 mg triazolam or 15 mg quazepam, with or without GFJ. Each trial was performed using an open, randomized, cross-over design with an interval of more than 2 weeks between trials. Blood samples were obtained during the 24-h period immediately following the administration of each dose. Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and utilizing a visual analog scale.

Results

GFJ increased the plasma concentrations of both triazolam and quazepam and of the active metabolite of quazepam, 2-oxoquazepam. The area under the curve (AUC)(0–24) of triazolam significantly increased by 96% (p<0.05). The AUC(0–24) of quazepam (+38%) and 2-oxoquazepam (+28%) also increased; however, these increases were not significantly different from those of triazolam. GFJ deteriorated the performance of the subjects in the DSST after the triazolam dose (−11 digits at 2 h after the dose, p<0.05), but not after the quazepam dose. Triazolam and quazepam produced similar sedative-like effects, none of which were enhanced by GFJ.

Conclusion

These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Edgar B, Bailey D, Bergstrand R, Johnsson G, Regardh CG (1992) Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance. Eur J Clin Pharmacol 42:313–317

    Article  PubMed  CAS  Google Scholar 

  2. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL (1996) Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 59:383–388

    Article  PubMed  CAS  Google Scholar 

  3. Ducharme MP, Warbasse LH, Edwards DJ (1995) Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 57:485–491

    Article  PubMed  CAS  Google Scholar 

  4. Lilja JJ, Kivistö KT, Neuvonen PJ (1998) Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 64:477–483

    Article  PubMed  CAS  Google Scholar 

  5. Lown KS, Bailey DG, Fontana RJ, Janardan JK, Adair CH, Fortlage LA, Brown MB, Guo W, Watkins PB (1997) Grapefruit juice increases felodipine oral bioavailability in human by decreasing intestinal CYP3A protein expression. J Clin Invest 99:2545–2553

    Article  PubMed  CAS  Google Scholar 

  6. Fukuda K, Ohta T, Oshima Y, Ohashi N, Yoshikawa M, Yamazoe Y (1997) Specific CYP3A4 inhibitors in grapefruit juice: furanocoumarin dimers as components of drug inhibition. Pharmacogenetics 7:391–396

    Article  PubMed  CAS  Google Scholar 

  7. Paine MF, Criss AB, Watkins PB (2004) Two major grapefruit juice components differ in intestinal CYP3A4 inhibition kinetics and binding properties. Drug Metab Dispos 32:1146–1153

    Article  PubMed  CAS  Google Scholar 

  8. Moltke LL von, Greenblatt DJ, Harmatz JS, Duan SX, Harrel JM, Catreau-Bibbo NM, Pritchard GA, Wright CE, Shader RI (1996) Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 276:370–379

    PubMed  Google Scholar 

  9. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ (1995) Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther 58:127–131

    Article  PubMed  CAS  Google Scholar 

  10. Lilja JJ, Kivistö KT, Backman JT, Neuvonen PJ (2000) Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life. Eur J Clin Pharmacol 56:411–415

    Article  PubMed  CAS  Google Scholar 

  11. Fujisaki H, Hirotsu K, Ogawa T, Mizuki K, Mizuta H, Arima N (2001) Metabolism of quazepam and its metabolites in humans: Identification of metabolic enzymes and evaluation of drug interaction in vitro (in Japanese with English abstract). Yakubutsudoutai (Xenobio Metabol Dispos) 16:558–568

    CAS  Google Scholar 

  12. Nasu K, Kubota T, Ishizaki T (1997) Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 7:405–409

    Article  PubMed  CAS  Google Scholar 

  13. Sostmann HJ, Sostmann H, Crevoisier C, Bircher J (1989) Dose equivalence of midazolam and triazolam: A psychometric study based on flicker sensitivity, reaction time and digit symbol substitution test. Eur J Clin Pharmacol 36:181–187

    Article  PubMed  CAS  Google Scholar 

  14. Chung M, Hilbert JM, Gural RP, Radwaniski E, Symchowicz S, Zampaglinone N (1984) Multiple-dose quazepam kinetics. Clin Pharmacol Ther 35:520–524

    Article  PubMed  CAS  Google Scholar 

  15. Hilbert JM, Chung M, Maier G, Grural R, Symchowicz S, Zampaglinone N (1984) Effect of sleep on quazepam kinetics. Clin Pharmacol Ther 36:99–104

    Article  PubMed  CAS  Google Scholar 

  16. Vanakoski J, Mattila MJ, Seppälä T (1996) Grapefruit juice does not enhance the effects of midazolam and triazolam in man. Eur J Clin Pharmacol 50:501–508

    Article  PubMed  CAS  Google Scholar 

  17. Roth TG, Roehrs TA, Koshorek GL, Greenblatt DJ, Rosenthal LD (1997) Hypnotic effects of low doses of quazepam in older insomniacs. J Clin Psychopharmacol 17:401–406

    Article  PubMed  CAS  Google Scholar 

  18. Nikaido AM, Ellinwood EH Jr (1987) Comparison of the effects of quazepam and triazolam on cognitive-neuromotor performance. Psychopharmacology 92:459–464

    Article  PubMed  CAS  Google Scholar 

  19. Goldstein JA, de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285–299

    Article  PubMed  CAS  Google Scholar 

  20. Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349–355

    Article  PubMed  CAS  Google Scholar 

  21. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (1996) The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6:341–349

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms. Junko Koyano, Hiroko Susuki and Mariko Hojo for their technical assistance.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical School, 3311-1 Minamikawachi, Tochigi, 329-0498, Japan

    Koh-ichi Sugimoto, Nobutaka Araki, Masami Ohmori, Ken-ichi Harada, Yimin Cui, Shuichi Tsuruoka, Atsuhiro Kawaguchi & Akio Fujimura

Authors
  1. Koh-ichi Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobutaka Araki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masami Ohmori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken-ichi Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yimin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuichi Tsuruoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atsuhiro Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akio Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akio Fujimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugimoto, Ki., Araki, N., Ohmori, M. et al. Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam. Eur J Clin Pharmacol 62, 209–215 (2006). https://doi.org/10.1007/s00228-005-0071-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-005-0071-1

Keywords

Search

Navigation