Skip to main content
SpringerLink
Log in

Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese

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

Abstract

Introduction

The aim of therapeutic regimens using proton pump inhibitors (PPIs) in patients with acid-related diseases is to potently inhibit acid secretion for the full 24 h. However, optimum treatment is still unclear because the pharmacodynamics of PPIs differ among CYP2C19 genotypes and most of the previous studies have had loss of sample power.

Methods

Using pH monitoring, we compared acid inhibition at standard dosage of omeprazole (20 mg, 50 times), lansoprazole (30 mg, 68 times), and rabeprazole (10 mg, 65 times) in Helicobacter pylori-negative healthy young Japanese volunteers.

Results

Median pH with rabeprazole was 5.4 (3.3–7.5), which was significantly greater than with either omeprazole [4.4 (2.1–7.3)] or lansoprazole [4.8 (3.5–6.4)] (both P < 0.05). Median 24-h pH differed among the different CYP2C19 genotypes in all three PPIs. In CYP2C19 extensive metabolizers (EMs), the genotype that is refractory to PPI treatment, median pH with omeprazole, lansoprazole, and rabeprazole was 3.8 (2.1–4.4), 4.5 (3.5–5.3) and 4.8 (3.3–7.5), respectively.

Discussion

Treatment with the selected PPIs at their standard dosages had difficulty maintaining acid inhibition for a full 24 h, especially in CYP2C19 EM. However, rabeprazole has the merit of less influence of CYP2C19 genotype compared with the other PPIs.

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

Abbreviations

CYP2C19:

S-mephenytoin 4′-hydroxylase

EM:

Extensive metabolizer

IM:

Intermediate metabolizer

PPI:

Proton pump inhibitor

PM:

Poor metabolizer

References

  1. Barer D, Ogilvie A, Henry D et al (1983) Cimetidine and tranexamic acid in the treatment of acute upper-gastrointestinal-tract bleeding. N Engl J Med 308:1571–1575

    Article  CAS  PubMed  Google Scholar 

  2. Bell NJ, Burget D, Howden CW et al (1992) Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 51(Suppl 1):59–67

    Article  PubMed  Google Scholar 

  3. Sugimoto M, Nishino M, Kodaira C et al (2011) Impact of acid inhibition on esophageal mucosal injury induced by low-dose aspirin. Digestion 85:9–17. doi:10.1159/000329295

    Article  PubMed  Google Scholar 

  4. Walsh JH, Peterson WL (1995) The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med 333:984–991

    Article  CAS  PubMed  Google Scholar 

  5. Furuta T, Sagehashi Y, Shirai N et al (2005) Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection. Clin Gastroenterol Hepatol 3:564–573

    Article  CAS  PubMed  Google Scholar 

  6. Furuta T, Shirai N, Watanabe F et al (2002) Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther 72:453–460

    Article  CAS  PubMed  Google Scholar 

  7. Sugimoto M, Furuta T, Shirai N et al (2007) Evidence that the degree and duration of acid suppression are related to Helicobacter pylori eradication by triple therapy. Helicobacter 12:317–323

    Article  CAS  PubMed  Google Scholar 

  8. 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  CAS  PubMed  Google Scholar 

  9. Horai Y, Kimura M, Furuie H et al (2001) Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes. Aliment Pharmacol Ther 15:793–803

    Article  CAS  PubMed  Google Scholar 

  10. Shirai N, Furuta T, Moriyama Y et al (2001) Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 15:1929–1937

    Article  CAS  PubMed  Google Scholar 

  11. Shirai N, Furuta T, Xiao F et al (2002) Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups. Aliment Pharmacol Ther 16:837–846

    Article  CAS  PubMed  Google Scholar 

  12. Sugimoto M, Furuta T, Shirai N et al (2004) Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status. Clin Pharmacol Ther 76:290–301

    Article  CAS  PubMed  Google Scholar 

  13. Chang M, Dahl ML, Tybring G et al (1995) Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5:358–363

    Article  CAS  PubMed  Google Scholar 

  14. Kubota T, Chiba K, Ishizaki T (1996) Genotyping of S-mephenytoin 4′-hydroxylation in an extended Japanese population. Clin Pharmacol Ther 60:661–666

    Article  CAS  PubMed  Google Scholar 

  15. Furuta T, Ohashi K, Kosuge K et al (1999) CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65:552–561

    Article  CAS  PubMed  Google Scholar 

  16. Furuta T, Shirai N, Takashima M et al (2001) Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 11:341–348

    Article  CAS  PubMed  Google Scholar 

  17. Sugimoto M, Furuta T, Shirai N et al (2005) Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes. Clin Pharmacol Ther 77:302–311

    Article  CAS  PubMed  Google Scholar 

  18. Hatlebakk JG, Katz PO, Castell DO (1999) Medical therapy. Management of the refractory patient. Gastroenterol Clin N Am 28:847–860

    Article  CAS  Google Scholar 

  19. Joh T, Miwa H, Higuchi K et al (2007) Validity of endoscopic classification of nonerosive reflux disease. J Gastroenterol 42:444–449

    Article  PubMed  Google Scholar 

  20. Miwa H, Sasaki M, Furuta T et al (2007) Efficacy of rabeprazole on heartburn symptom resolution in patients with non-erosive and erosive gastro-oesophageal reflux disease: a multicenter study from Japan. Aliment Pharmacol Ther 26:69–77

    Article  CAS  PubMed  Google Scholar 

  21. Sugimoto M, Nishino M, Kodaira C et al (2011) Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy. World J Gastroenterol 17:1858–1865. doi:10.3748/wjg.v17.i14.1858

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Klinkenberg-Knol EC, Festen HP, Jansen JB et al (1994) Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 121:161–167

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Katsube T, Adachi K, Kawamura A et al (2000) Helicobacter pylori infection influences nocturnal gastric acid breakthrough. Aliment Pharmacol Ther 14:1049–1056

    Article  CAS  PubMed  Google Scholar 

  26. Nishino M, Sugimoto M, Kodaira C et al (2010) Relationship between low-dose aspirin-induced gastric mucosal injury and intragastric pH in healthy volunteers. Dig Dis Sci 55:1627–1636. doi:10.1007/s10620-009-0920-3, CDAI: 19672708

    Article  CAS  PubMed  Google Scholar 

  27. Kodaira C, Sugimoto M, Nishino M et al (2009) Effect of MDR1 C3435T polymorphism on lansoprazole in healthy Japanese subjects. Eur J Clin Pharmacol 65:593–600. doi:10.1007/s00228-009-0625-8, CDAI: 19238367

    Article  CAS  PubMed  Google Scholar 

  28. Furuta T, Shirai N, Xiao F et al (2001) Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19. Clin Pharmacol Ther 70:484–492, CDAI: 11719736

    Article  CAS  PubMed  Google Scholar 

  29. Furuta T, Shirai N, Kodaira M et al (2007) Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther 81:521–528, CDAI: 17215846

    Article  CAS  PubMed  Google Scholar 

  30. Uotani T, Sugimoto M, Nishino M et al (2012) Ability of rabeprazole to prevent gastric mucosal damage from clopidogrel and low doses of aspirin depends on CYP2C19 genotype. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2012.04.016, CDAI: 22542748

    PubMed  Google Scholar 

  31. Kurata S, Kanagawa T, Yamada K et al (2001) Fluorescent quenching-based quantitative detection of specific DNA/RNA using a BODIPY((R)) FL-labeled probe or primer. Nucleic Acids Res 29:E34, CDAI: 11239011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Torimura M, Kurata S, Yamada K et al (2001) Fluorescence-quenching phenomenon by photoinduced electron transfer between a fluorescent dye and a nucleotide base. Anal Sci Int J Jpn Soc Anal Chem 17:155–160, CDAI: 11993654

    CAS  Google Scholar 

  33. Furuta T, Soya Y, Sugimoto M et al (2013) Rapid automated genotyping of CYP2C19 and Helicobacter pylori 23S rRNA gene in gastric juice. J Gastroenterol Hepatol Res 2:506–512

    Google Scholar 

  34. De Morais SM, Wilkinson GR, Blaisdell J et al (1994) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598, CDAI: 7969038

    PubMed  Google Scholar 

  35. Adachi K, Fujishiro H, Katsube T et al (2001) Predominant nocturnal acid reflux in patients with Los Angeles grade C and D reflux esophagitis. J Gastroenterol Hepatol 16:1191–1196, CDAI: 11903734

    Article  CAS  PubMed  Google Scholar 

  36. Yasuda S, Horai Y, Tomono Y et al (1995) Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther 58:143–154, CDAI: 7648764

    Article  CAS  PubMed  Google Scholar 

  37. Kawamura M, Ohara S, Koike T et al (2003) The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19 polymorphism. Aliment Pharmacol Ther 17:965–973, CDAI: 12656699

    Article  CAS  PubMed  Google Scholar 

  38. Kawamura M, Ohara S, Koike T et al (2007) Cytochrome P450 2C19 polymorphism influences the preventive effect of lansoprazole on the recurrence of erosive reflux esophagitis. J Gastroenterol Hepatol 22:222–226. doi:10.1111/j.1440-1746.2006.04419.x, CDAI: 17295875

    Article  CAS  PubMed  Google Scholar 

  39. Sim SC, Risinger C, Dahl ML et al (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113, CDAI: 16413245

    Article  CAS  PubMed  Google Scholar 

  40. Sugimoto K, Uno T, Yamazaki H et al (2008) Limited frequency of the CYP2C19*17 allele and its minor role in a Japanese population. Br J Clin Pharmacol 65:437–439. doi:10.1111/j.1365-2125.2007.03057.x, CDAI: 2291245

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Kinoshita Y, Hongo M (2012) Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory to standard once-daily administration of PPI: the Japan-based TWICE study. Am J Gastroenterol 107:522–530. doi:10.1038/ajg.2012.19, CDAI: 22433921

    Article  CAS  PubMed  Google Scholar 

  42. Sugimoto M, Shirai N, Nishino M et al (2012) Rabeprazole 10 mg q.d.s. decreases 24-h intragastric acidity significantly more than rabeprazole 20 mg b.d. or 40 mg o.m., overcoming CYP2C19 genotype. Aliment Pharmacol Ther 36:627–634. doi:10.1111/apt.12014, CDAI: 22882464

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (22790640 and 24590912).

Conflicts of interest

None of the authors has any conflict of interest related to this study.

Author information

Authors and Affiliations

  1. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Mitsushige Sugimoto, Chise Kodaira, Takahiro Uotani, Shu Sahara, Hitomi Ichikawa, Takuma Kagami & Ken Sugimoto

  2. Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takahisa Furuta

  3. Department of Gastroenterology, Enshu General Hospital, Shizuoka, Japan

    Naohito Shirai & Masafumi Nishino

Authors
  1. Mitsushige Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naohito Shirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masafumi Nishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chise Kodaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takahiro Uotani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shu Sahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hitomi Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuma Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ken Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takahisa Furuta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitsushige Sugimoto.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sugimoto, M., Shirai, N., Nishino, M. et al. Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese. Eur J Clin Pharmacol 70, 1073–1078 (2014). https://doi.org/10.1007/s00228-014-1713-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-014-1713-y

Keywords

Search

Navigation