Skip to main content
SpringerLink
Log in

Dose–response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes

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

Abstract

Purpose

This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole.

Methods

Eight individuals of each of the three genotypes of CYP2C19—homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)—were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5.

Results

A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (−5.0% − 21.0%), 28.7% (15.7% − 41.6%), and 16.9% (3.9% − 29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC0-t) and the pH 4 holding time could be described using a sigmoid maximum effect (Emax) model.

Conclusions

Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion.

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
Fig. 3

Similar content being viewed by others

References

  1. Sachs G (1997) Proton pump inhibitors and acid-related diseases. Pharmacotherapy 17:22–37

    PubMed  CAS  Google Scholar 

  2. Fass R, Shapiro M, Dekel R, Sewell J (2005) Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease—where next? Aliment Pharmacol Ther 22:79–94

    Article  PubMed  CAS  Google Scholar 

  3. Peghini PL, Katz PO, Bracy NA, Castell DO (1998) Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 93:763–767

    Article  PubMed  CAS  Google Scholar 

  4. Hatlebakk JG, Katz PO, Kuo B, Castell DO (1998) Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Aliment Pharmacol Ther 12:1235–1240

    Article  PubMed  CAS  Google Scholar 

  5. Peghini PL, Katz PO, Castell DO (1998) Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 115:1335–1339

    Article  PubMed  CAS  Google Scholar 

  6. Adachi K, Fujishiro H, Katsube T, Yuki M, Ono M, Kawamura A, Rumi MA, Watanabe M, Kinoshita Y (2001) Predominant nocturnal acid reflux in patients with Los Angeles grade C and D reflux esophagitis. J Gastroenterol Hepatol 16:1191–1196

    Article  PubMed  CAS  Google Scholar 

  7. Pace F, Pallotta S, Casalini S, Porro GB (2007) A review of rabeprazole in the treatment of acid-related diseases. Ther Clin Risk Manag 3:363–379

    PubMed  CAS  Google Scholar 

  8. Lew EA, Barbuti RC, Kovacs TO, Sytnic B, Humphries TJ, Walsh JH (1998) An ascending single-dose safety and tolerance study of an oral formulation of rabeprazole (E3810). Aliment Pharmacol Ther 12:667–672

    Article  PubMed  CAS  Google Scholar 

  9. Williams MP, Blanshard C, Millson C, Sercombe J, Pounder RE (2000) A placebo-controlled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects. Aliment Pharmacol Ther 14:691–699

    Article  PubMed  CAS  Google Scholar 

  10. Ohning GV, Barbuti RC, Kovacs TO, Sytnik B, Humphries TJ, Walsh JH (2000) Rabeprazole produces rapid, potent, and long-acting inhibition of gastric acid secretion in subjects with Helicobacter pylori infection. Aliment Pharmacol Ther 14:701–708

    Article  PubMed  CAS  Google Scholar 

  11. Robinson M, Maton PN, Rodriguez S, Greenwood B, Humphries TJ (1997) Effects of oral rabeprazole on oesophageal and gastric pH in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 11:973–980

    Article  PubMed  CAS  Google Scholar 

  12. Shimatani T, Inoue M, Kuroiwa T, Horikawa Y (2004) Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression. Aliment Pharmacol Ther 19:113–122

    Article  PubMed  CAS  Google Scholar 

  13. Sugimoto M, Furuta T, Shirai N, Kajimura M, Hishida A, Sakurai M, Ohashi K, Ishizaki T (2004) Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2 C19 genotype status. Clin Pharmacol Ther 76:290–301

    Article  PubMed  CAS  Google Scholar 

  14. Kinoshita Y, Ashida K, Hongo M; Japan Rabeprazole Study Group for NERD (2011) Randomised clinical trial: a multicentre, double-blind, placebo-controlled study on the efficacy and safety of rabeprazole 5 mg or 10 mg once daily in patients with non-erosive reflux disease. Aliment Pharmacol Ther 33:213–224

    Article  Google Scholar 

  15. Andersson T (1996) Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 31:9–28

    Article  PubMed  CAS  Google Scholar 

  16. Shirai N, Furuta T, Moriyama Y, Okochi H, Kobayashi K, Takashima M, Xiao F, Kosuge K, Nakagawa K, Hanai H, Chiba K, Ohashi K, Ishizaki T (2001) Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 15:1929–1937

    Article  PubMed  CAS  Google Scholar 

  17. Shi S, Klotz U (2008) Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 64:935–951

    Article  PubMed  CAS  Google Scholar 

  18. Ishizaki T, Horai Y (1999) Review article: cytochrome P450 and the metabolism of proton pump inhibitors – emphasis on rabeprazole. Aliment Pharmacol Ther 13(Suppl 3):27–36

    Article  PubMed  CAS  Google Scholar 

  19. Yasuda S, Horai Y, Tomono Y, Nakai H, Yamato C, Manabe K, Kobayashi K, Chiba K, Ishizaki T (1995) Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4hydroxylation status. Clin Pharmacol Ther 58:143–154

    Article  PubMed  CAS  Google Scholar 

  20. Adachi K, Katsube T, Kawamura A, Takashima T, Yuki M, Amano K, Ishihara S, Fukuda R, Watanabe M, Kinoshita Y (2000) CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther 14:1259–1266

    Article  PubMed  CAS  Google Scholar 

  21. Horai Y, Kimura M, Furuie H, Matsuguma K, Irie S, Koga Y, Nagahama T, Murakami M, Matsui T, Yao T, Urae A, Ishizaki T (2001) Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes. Aliment Pharmacol Ther 15:793–803

    Article  PubMed  CAS  Google Scholar 

  22. Ieiri I, Kishimoto Y, Okochi H, Momiyama K, Morita T, Kitano M et al (2001) Comparison of the kinetic disposition of and serum gastrin change by lansoprazole versus rabeprazole during an 8-day dosing scheme in relation to CYP2C19 polymorphism. Eur J Clin Pharmacol 57:485–492

    Article  PubMed  CAS  Google Scholar 

  23. Bell NJ, Hunt RH (1992) Role of gastric acid suppression in the treatment of gastro-oesophageal reflux disease. Gut 33:118–124

    Article  PubMed  CAS  Google Scholar 

  24. Katz PO, Johnson DA, Levine D, Rohss K, Junghard O, Astrand M, Nagy P (2010) A model of healing of Los Angeles grades C and D reflux oesophagitis: is there an optimal time of acid suppression for maximal healing? Aliment Pharmacol Ther 32:443–447

    Article  PubMed  CAS  Google Scholar 

  25. Klotz U (2006) Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther 44:297–302

    PubMed  CAS  Google Scholar 

  26. Andersson T, Rohss K, Bredberg E, Hassan-Alin M (2001) Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 15:1563–1569

    Article  PubMed  CAS  Google Scholar 

  27. Junghard O, Hassan-Alin M, Hasselgren G (2002) The effect of the area under the plasma concentration vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH. Eur J Clin Pharmacol 58:453–458

    Article  PubMed  CAS  Google Scholar 

  28. Gillen D, Wirz AA, Neithercut WD, Ardill JE, McColl KEL (1999) Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. Gut 44:468–475

    Article  PubMed  CAS  Google Scholar 

  29. Verdu EF, Armstrong D, Fraser R, Viani F, Idstrom JP, Cederberg C, Blum AL (1995) Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut 36:539–543

    Article  PubMed  CAS  Google Scholar 

  30. Verdu EF, Armstrong D, Idstrom JP, Labenz J, Stolte M, Dorta G, Börsch G, Blum AL (1995) Effect of curing Helicobacter pylori infection on intragastric pH during treatment with omeprazole. Gut 37:743–748

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The authors thank Dr. Y. Kinoshita of Shimane University Faculty of Medicine for his valuable comments. The authors also thank all contributing staff members in Sekino Clinical Pharmacology Clinic for their involvement in this study, and the project members in Eisai Co., Ltd., Tokyo, Japan for the preparation support of this paper. The preparation support was also provided by Eisai Inc., Woodcliff Lake, NJ, USA

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Japan Clinical Pharmacology, Clinical Pharmacology & Translational Medicine, Clinical Science, Scientific and Operational Clinical Support Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, Japan

    Yukio Horai

  2. Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, Japan

    Seiichi Hayato, Seiichiro Hojo, Hiroki Okawa, Hiroaki Abe, Nobuyuki Sugisaki, Masahiro Munesue & Yukio Horai

  3. Sekino Clinical Pharmacology Clinic, 3-28-3 Ikebukuro, Toshima-ku, Tokyo, 171-0014, Japan

    Setsuo Hasegawa

  4. Department of Laboratory Medicine, Daisan Hospital, The Jikei University School of Medicine, 4-11-1 Izumihonchyo, Komae, Tokyo, 201-8601, Japan

    Akihiro Ohnishi

Authors
  1. Seiichi Hayato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Setsuo Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seiichiro Hojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroki Okawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroaki Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuyuki Sugisaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masahiro Munesue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukio Horai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akihiro Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yukio Horai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hayato, S., Hasegawa, S., Hojo, S. et al. Dose–response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes. Eur J Clin Pharmacol 68, 579–588 (2012). https://doi.org/10.1007/s00228-011-1164-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-011-1164-7

Keywords

Search

Navigation