Skip to main content
SpringerLink
Log in

Prediction of herb–drug interaction between hyperforin and sedative hypnotics (zolpidem, alprazolam, and midazolam) using physiologically-based pharmacokinetic modeling

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

This study investigates the interactions between various doses of hyperforin, a key compound in St. John’s Wort, and sedative hypnotics such as zolpidem, alprazolam, and midazolam. Since St John’s Wort is known to be an inducer of cytochrome P450 (CYP) 3A4, co-administration with drugs metabolized by CYP3A4 has been contraindicated.

Objective

We studied the risks of combination use and the possibility of safe combination by simulating the interaction of hyperforin, a key compound in St. John’s Wort, with drugs metabolized by CYP3A4 that can be used to relieve various symptoms of depression. Understanding these interactions is crucial for optimizing the treatment of depression and associated symptoms.

Results

The hyperforin physiologically based pharmacokinetic (PBPK) model was validated against clinical data, and PBPK models for zolpidem, alprazolam, and midazolam were used to predict herb–drug interactions. The simulations with a two-week co-administration scenario showed that hyperforin potentially acts as a weak inducer (hyperforin dose 2–20 mg, 3 times a day, AUC ratio 0.8–0.68) of 10 mg zolpidem metabolism, with sex-dependent interactions largely unaffected. However, the pharmacokinetics of alprazolam at doses of 0.25, 0.5, and 1 mg were minimally impacted (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.96–0.87). In the case of 7.5 mg midazolam, hyperforin acted as a moderate to strong inducer (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.26–0.20), even at low doses.

Conclusions

These findings emphasize the importance of careful monitoring and dose adjustments when using hyperforin and sedative hypnotics together. This study provided insights into co-administration of hyperforin and sedative hypnotics, facilitating the safe and effective use of these medications. Based on these results, it is necessary to know the possibility of safer drug combination, and to conduct clinical research and verification on this.

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  • Adiwidjaja J, Boddy AV, McLachlan AJ (2019) Physiologically based pharmacokinetic modelling of hyperforin to predict drug interactions with St John’s wort. Clin Pharmacokinet 58:911–926

    Article  CAS  PubMed  Google Scholar 

  • Ait-Daoud N, Hamby AS, Sharma S, Blevins D (2018) A review of alprazolam use, misuse, and withdrawal. J Addict Med 12:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JN et al (2016) A systematic review of St. John’s wort for major depressive disorder. Syst Rev 5:1–25

    Article  Google Scholar 

  • Arold G, Donath F, Maurer A, Diefenbach K, Bauer S et al (2005) No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extract. Planta Med 71:331–337

    Article  CAS  PubMed  Google Scholar 

  • Asnis GM, Chakraburtty A, DuBoff EA, Krystal A, Londborg PD et al (1999) Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 60:668–676

    Article  CAS  PubMed  Google Scholar 

  • Biber A, Fischer H, Römer A, Chatterjee S (1998) Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry 31:36–43

    Article  CAS  PubMed  Google Scholar 

  • Biro P, Weidmann G, Pietzsch S, Alon E, Brugger P (1997) The dose-dependent effects of oral premedication with midazolam. Anasthesiol Intensivmed Notfallmed Schmerzther AINS 32:672–677

    Article  CAS  PubMed  Google Scholar 

  • Blake MJ, Trinder JA, Allen NB (2018) Mechanisms underlying the association between insomnia, anxiety, and depression in adolescence: implications for behavioral sleep interventions. Clin Psychol Rev 63:25–40

    Article  PubMed  Google Scholar 

  • Bonnet MH, Kramer M, Roth T (1981) A dose response study of the hypnotic effectiveness of alprazolam and diazepam in normal subjects. Psychopharmacology 75:258–261

    Article  CAS  PubMed  Google Scholar 

  • Cantoni L, Rozio M, Mangolini A, Hauri L, Caccia S (2003) Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse. Toxicol Sci 75:25–30

    Article  CAS  PubMed  Google Scholar 

  • Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ (2019) Understanding drug interactions with St John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol 71:129–138

    Article  CAS  PubMed  Google Scholar 

  • Crestani F, Martin JR, Möhler H, Rudolph U (2000) Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 131:1251–1254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donato MT, Hallifax D, Picazo L, Castell JV, Houston JB et al (2010) Metabolite formation kinetics and intrinsic clearance of phenacetin, tolbutamide, alprazolam, and midazolam in adenoviral cytochrome P450-transfected HepG2 cells and comparison with hepatocytes and in vivo. Drug Metab Dispos 38:1449–1455

    Article  CAS  PubMed  Google Scholar 

  • Dresser GK, Schwarz UI, Wilkinson GR, Kim RB (2003) Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther 73:41–50

    Article  CAS  PubMed  Google Scholar 

  • Dundee J, Halliday N, Harper K, Brogden R (1984) Midazolam: a review of its pharmacological properties and therapeutic use. Drugs 28:519–543

    Article  CAS  PubMed  Google Scholar 

  • Greenblatt DJ, Harmatz JS, von Moltke LL, Ehrenberg BL, Harrel L et al (1998) Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther 64:553–561

    Article  CAS  PubMed  Google Scholar 

  • Greenblatt DJ, Harmatz JS, Singh NN, Steinberg F, Roth T et al (2014) Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration. J Clin Pharmacol 54:282–290

    Article  CAS  PubMed  Google Scholar 

  • Hoehns J, Perry P (1993) Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm 12:814–828

    CAS  PubMed  Google Scholar 

  • Hojo Y, Echizenya M, Ohkubo T, Shimizu T (2011) Drug interaction between St John’s wort and zolpidem in healthy subjects. J Clin Pharm Ther 36:711–715

    Article  CAS  PubMed  Google Scholar 

  • Huang S-M, Abernethy DR, Wang Y, Zhao P, Zineh I (2013) The utility of modeling and simulation in drug development and regulatory review. J Pharm Sci 102:2912–2923

    Article  CAS  PubMed  Google Scholar 

  • Imai H, Kotegawa T, Tsutsumi K, Morimoto T, Eshima N et al (2008) The recovery time-course of CYP3A after induction by St John’s wort administration. Br J Clin Pharmacol 65:701–707

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS et al (1998) Single-dose pharmacokinetics and pharmacodynamics of alprazolam in elderly and young subjects. J Clin Pharmacol 38:14–21

    Article  CAS  PubMed  Google Scholar 

  • Kelly T, Foltin R, Serpick E, Fischman M (1997) Behavioral effects of alprazolam in humans. Behav Pharmacol 8:47–57

    Article  CAS  PubMed  Google Scholar 

  • Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R et al (2004) Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures. Drug Metab Dispos 32:512–518

    Article  CAS  PubMed  Google Scholar 

  • Laakmann G, Schüle C, Baghai T, Kieser M (1998) St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 31:54–59

    Article  CAS  PubMed  Google Scholar 

  • Langtry HD, Benfield P (1990) Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 40:291–313

    Article  CAS  PubMed  Google Scholar 

  • Licata SC, Jensen JE, Conn NA, Winer JP, Lukas SE (2014) Zolpidem increases GABA in depressed volunteers maintained on SSRIs. Psychiatry Res Neuroimag 224:28–33

    Article  Google Scholar 

  • Mai I, Bauer S, Perloff ES, Johne A, Uehleke B et al (2004) Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interaction. Clin Pharmacol Ther 76:330–340

    Article  CAS  PubMed  Google Scholar 

  • Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y et al (2003) Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 290:1500–1504

    Article  CAS  PubMed  Google Scholar 

  • Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ et al (2000) St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci 97:7500–7502

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller SC, Majcher-Peszynska J, Uehleke B, Klammt S, Mundkowski RG et al (2006) The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose. Eur J Clin Pharmacol 62:29–36

    Article  CAS  PubMed  Google Scholar 

  • Nagai M, Hosaka T, Satsukawa M, Yoshinari K (2018) Characterization of CYP2C induction in cryopreserved human hepatocytes and its application in the prediction of the clinical consequences of the induction. J Pharm Sci 107:2479–2488

    Article  CAS  PubMed  Google Scholar 

  • Nicolussi S, Drewe J, Butterweck V, Meyerzu Schwabedissen HE (2020) Clinical relevance of St. John’s wort drug interactions revisited. Br J Pharmacol 177:1212–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obach RS (2000) Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 294:88–95

    CAS  PubMed  Google Scholar 

  • Polasek TM, Sadagopal JS, Elliot DJ, Miners JO (2010) In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A. Eur J Clin Pharmacol 66:275–283

    Article  CAS  PubMed  Google Scholar 

  • Reves Jd, Fragen RJ, Vinik HR, Greenblatt DJ (1985) Midazolam: pharmacology and uses. Anesthesiology 62:310–324

    Article  CAS  PubMed  Google Scholar 

  • Riba J, Rodríguez-Fornells A, Urbano G, Morte A, Antonijoan R et al (2001) Differential effects of alprazolam on the baseline and fear-potentiated startle reflex in humans: a dose-response study. Psychopharmacology 157:358–367

    Article  CAS  PubMed  Google Scholar 

  • Rodgers T, Rowland M (2007) Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res 24:918–933

    Article  CAS  PubMed  Google Scholar 

  • Schulz H-U, Schürer M, Bässler D, Weiser D (2005) Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers. Arzneimittelforschung 55:561–568

    CAS  PubMed  Google Scholar 

  • Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M (2017) Clinical risks of St John’s Wort (Hypericum perforatum) co-administration. Expert Opin Drug Metab Toxicol 13:1047–1062

    Article  CAS  PubMed  Google Scholar 

  • Solomon D, Adams J, Graves N (2013) Economic evaluation of St. John’s wort (Hypericum perforatum) for the treatment of mild to moderate depression. J Affect Disord 148:228–234

    Article  PubMed  Google Scholar 

  • Tiller JW (2013) Depression and anxiety. Med J Aust 199:S28–S31

    Article  PubMed  Google Scholar 

  • Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A (2007) Prediction of intestinal first-pass drug metabolism. Curr Drug Metab 8:676–684

    Article  CAS  PubMed  Google Scholar 

  • Yeo KR, Jamei M, Rostami-Hodjegan A (2013) Predicting drug–drug interactions: application of physiologically based pharmacokinetic models under a systems biology approach. Expert Rev Clin Pharmacol 6:143–157

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (number: HF20C0212). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government [MSIT] (RS-2023-00218419) (NRF-2022R1I1A3053818). This work was also supported by the research grant of the Gyeongsang National University in 2023.

Author information

Author notes

  1. Anna Shin and Boyun Jang contributed equally to the work.

Authors and Affiliations

  1. IntegroMediLab Co., Ltd., 428-Bonguan, Chungmuro Building of Dongguk University, 2, Toegye-Ro 36-Gil, Jung-Gu, Seoul, Korea

    Anna Shin, Boyun Jang, Sunyoung Cho & Youngsoo Kim

  2. Department of Pediatrics, Department of Pharmaceutical Medicine and Regulatory Science, College of Medicine, Yonsei University, Seoul, 03722, Korea

    Min Soo Park

  3. Department of Veterinary Physiology, College of Veterinary Medicine, Gyeongsang National University, Jinju, 52828, Korea

    Kwang-Il Park

  4. AI-Bio Convergence DDI Basic Research Laboratory (BRL), School of Korean Medicine, Dongguk University, Gyeongju, 38066, Korea

    Young Woo Kim

  5. Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, 03722, Korea

    Choon Ok Kim

Authors
  1. Anna Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boyun Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sunyoung Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Youngsoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Soo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwang-Il Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Young Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Choon Ok Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AS, BJ, SC, YK, MSP, KIP, YWK and COK designed the study, AS and BJ performed the investigation, AS, BJ, SC and YK prepared the original draft for publication, AS, BJ, SC, YK, MSP, YWK and COK edited and reviewed the draft of the manuscript, KIP, YWK and COK contributed to funding acquisition. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Kwang-Il Park, Young Woo Kim or Choon Ok Kim.

Ethics declarations

Conflict of interest

Anna Shin declares that she has no conflict of interest. Boyun Jang declares that she has no conflict of interest. Sunyoung Cho declares that she has no conflict of interest. Youngsoo Kim declares that he has no conflict of interest. Min Soo Park declares that he has no conflict of interest. Kwang-Il Park declares that he has no conflict of interest. Young Woo Kim declares that he has no conflict of interest. Choon Ok Kim declares that she has no conflict of interest.

Ethical approval

This manuscript does not include the experiments on human subjects or animals.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 40 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, A., Jang, B., Cho, S. et al. Prediction of herb–drug interaction between hyperforin and sedative hypnotics (zolpidem, alprazolam, and midazolam) using physiologically-based pharmacokinetic modeling. Mol. Cell. Toxicol. 20, 431–439 (2024). https://doi.org/10.1007/s13273-024-00427-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-024-00427-9

Keywords

Search

Navigation