Current Gastroenterology Reports

, Volume 10, Issue 6, pp 528–534 | Cite as

Pharmacology of proton pump inhibitors

  • Jai Moo Shin
  • George Sachs


The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. PPIs are acid-activated prodrugs that convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last much longer than their plasma half-life. However, the short half-life of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori.


Omeprazole Proton Pump Inhibitor Acid Secretion Lansoprazole Parietal Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Forte JG, Forte TM, Black JA, et al.: Correlation of parietal cell structure and function. J Clin Gastroenterol 1983, 5(Suppl 1):17–27.PubMedCrossRefGoogle Scholar
  2. 2.
    Sawaguchi A, Aoyama F, Ide S, et al.: The cryofixation of isolated rat gastric mucosa provides new insights into the functional transformation of gastric parietal cells: an in vitro experimental model study. Arch Histol Cytol 2005, 68:151–160.PubMedCrossRefGoogle Scholar
  3. 3.
    Sachs G, Chang HH, Rabon E, et al.: A nonelectrogenic H+ pump in plasma membranes of hog stomach. J Biol Chem 1976, 251:7690–7698.PubMedGoogle Scholar
  4. 4.
    Shull GE, Lingrel JB: Molecular cloning of the rat stomach (H + + K + )-ATPase. J Biol Chem 1986, 261:16788–16791.PubMedGoogle Scholar
  5. 5.
    Maeda M, Ishizaki J, Futai M: cDNA cloning and sequence determination of pig gastric (H+ + K+)-ATPase. Biochem Biophys Res Commun 1988, 157:203–209.PubMedCrossRefGoogle Scholar
  6. 6.
    Bamberg K, Mercier F, Reuben MA, et al.: cDNA cloning and membrane topology of the rabbit gastric H +/K +-ATPase alpha-subunit. Biochim Biophys Acta 1992, 1131:69–77.PubMedGoogle Scholar
  7. 7.
    Song I, Mortell MP, Gantz I, et al.: Molecular cloning and structural analysis of canine gastric H +,K +-ATPase. Biochem Biophys Res Commun 1993, 196:1240–1247.PubMedCrossRefGoogle Scholar
  8. 8.
    Maeda M, Oshiman K, Tamura S, et al.: Human gastric (H + + K +)-ATPase gene. Similarity to (Na + + K + )-ATPase genes in exon/intron organization but difference in control region. J Biol Chem 1990, 265:9027–9032.PubMedGoogle Scholar
  9. 9.
    Rabon EC, McFall TL, Sachs G: The gastric [H,K]ATPase: H +/ATP stoichiometry. J Biol Chem 1982, 257:6296–6299.PubMedGoogle Scholar
  10. 10.
    Munson K, Garcia R, Sachs G: Inhibitor and ion binding sites on the gastric H,K-ATPase. Biochemistry 2005, 44:5267–5284.PubMedCrossRefGoogle Scholar
  11. 11.
    Morii M, Yamauchi M, Ichikawa T, et al.: Involvement of the H3O +-Lys-164-Gln-161-Glu-345 charge transfer pathway in proton transport of gastric H +,K +-ATPase. J Biol Chem 2008, 283:16876–16884.PubMedCrossRefGoogle Scholar
  12. 12.
    Reuben MA, Lasater LS, Sachs G: Characterization of a beta subunit of the gastric H +/K +-transporting ATPase. Proc Natl Acad Sci U S A 1990, 87:6767–6771.PubMedCrossRefGoogle Scholar
  13. 13.
    Shull GE: cDNA cloning of the beta-subunit of the rat gastric H,K-ATPase. J Biol Chem 1990, 265:12123–12126.PubMedGoogle Scholar
  14. 14.
    Toh BH, Gleeson PA, Simpson RJ, et al.: The 60-to 90-kDa parietal cell autoantigen associated with autoimmune gastritis is a beta subunit of the gastric H +/K +-ATPase (proton pump). Proc Natl Acad Sci U S A 1990, 87:6418–6422.PubMedCrossRefGoogle Scholar
  15. 15.
    Vagin O, Denevich S, Sachs G: Plasma membrane delivery of the gastric H,K-ATPase: the role of beta-subunit glycosylation. Am J Physiol Cell Physiol 2003, 285:C968–C976.PubMedGoogle Scholar
  16. 16.
    Vagin O, Turdikulova S, Sachs G: The H,K-ATPase beta subunit as a model to study the role of N-glycosylation in membrane trafficking and apical sorting. J Biol Chem 2004, 279:39026–39034.PubMedCrossRefGoogle Scholar
  17. 17.
    Vagin O, Turdikulova S, Yakubov I, et al.: Use of the H,KATPase beta subunit to identify multiple sorting pathways for plasma membrane delivery in polarized cells. J Biol Chem 2005, 280:14741–14754.PubMedCrossRefGoogle Scholar
  18. 18.
    Munson K, Law RJ, Sachs G: Analysis of the gastric H,K ATPase for ion pathways and inhibitor binding sites. Biochemistry 2007, 46:5398–5417.PubMedCrossRefGoogle Scholar
  19. 19.
    Abe K, Kaya S, Taniguchi K, et al.: Evidence for a relationship between activity and the tetraprotomeric assembly of solubilized pig gastric H/K-ATPase. J Biochem (Tokyo) 2005, 138:293–301.Google Scholar
  20. 20.
    Shin JM, Grundler G, Senn-Bilfinger J, et al.: Functional consequences of the oligomeric form of the membrane-bound gastric H,K-ATPase. Biochemistry 2005, 44:16321–16332.PubMedCrossRefGoogle Scholar
  21. 21.
    Reenstra WW, Crothers J Jr, Forte JG: The conformation of H,K-ATPase determines the nucleoside triphosphate (NTP) selectivity for active proton transport. Biochemistry 2007, 46:10145–10152.PubMedCrossRefGoogle Scholar
  22. 22.
    Fellenius E, Berglindh T, Sachs G, et al.: Substituted benzimidazoles inhibit gastric acid secretion by blocking (H + + K + )ATPase. Nature 1981, 290:159–161.PubMedCrossRefGoogle Scholar
  23. 23.
    Shin JM, Homerin M, Domagala F, et al.: Characterization of the inhibitory activity of tenatoprazole on the gastric H +,K +-ATPase in vitro and in vivo. Biochem Pharmacol 2006, 71:837–849.PubMedCrossRefGoogle Scholar
  24. 24.
    Sachs G, Shin JM, Besancon M, et al.: The continuing development of gastric acid pump inhibitors. Aliment Pharmacol Ther 1993, 7(Suppl 1):4–12; discussion 29–31.PubMedGoogle Scholar
  25. 25.
    Shin JM, Besancon M, Simon A, et al.: The site of action of pantoprazole in the gastric H +/K +-ATPase. Biochim Biophys Acta 1993, 1148:223–233.PubMedCrossRefGoogle Scholar
  26. 26.
    Shin JM, Sachs G: Differences in binding properties of two proton pump inhibitors on the gastric H +,K +-ATPase in vivo. Biochem Pharmacol 2004, 68:2117–2127.PubMedCrossRefGoogle Scholar
  27. 27.
    Besancon M, Shin JM, Mercier F, et al.: Membrane topology and omeprazole labeling of the gastric H +,K +-adenosinetriphosphatase. Biochemistry 1993, 32:2345–2355.PubMedCrossRefGoogle Scholar
  28. 28.
    Shin JM, Sachs G: Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 2002, 123:1588–1597.PubMedCrossRefGoogle Scholar
  29. 29.
    Gedda K, Scott D, Besancon M, et al.: Turnover of the gastric H +,K +-adenosine triphosphatase alpha subunit and its effect on inhibition of rat gastric acid secretion. Gastroenterology 1995, 109:1134–1141.PubMedCrossRefGoogle Scholar
  30. 30.
    Hunt RH, Armstrong D, Yaghoobi M, et al.: Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z. Aliment Pharmacol Ther 2008, 28:187–199.PubMedCrossRefGoogle Scholar
  31. 31.
    Wallmark B, Larsson H, Humble L: The relationship between gastric acid secretion and gastric H +,K +-ATPase activity. J Biol Chem 1985, 260:13681–13684.PubMedGoogle Scholar
  32. 32.
    Im WB, Blakeman DP, Davis JP: Irreversible inactivation of rat gastric (H +-K + )-ATPase in vivo by omeprazole. Biochem Biophys Res Commun 1985, 126:78–82.PubMedCrossRefGoogle Scholar
  33. 33.
    Ferron GM, McKeand W, Mayer PR: Pharmacodynamic modeling of pantoprazole’s irreversible effect on gastric acid secretion in humans and rats. J Clin Pharmacol 2001, 41:149–156.PubMedCrossRefGoogle Scholar
  34. 34.
    Dammann HG, Burkhardt F: Pantoprazole versus omeprazole: influence on meal-stimulated gastric acid secretion. Eur J Gastroenterol Hepatol 1999, 11:1277–1282.PubMedCrossRefGoogle Scholar
  35. 35.
    Katashima M, Yamamoto K, Tokuma Y, et al.: Comparative pharmacokinetic/pharmacodynamic analysis of proton pump inhibitors omeprazole, lansoprazole and pantoprazole, in humans. Eur J Drug Metab Pharmacokinet 1998, 23:19–26.PubMedGoogle Scholar
  36. 36.
    Lind T, Rydberg L, Kyleback A, et al.: Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000, 14:861–867.PubMedCrossRefGoogle Scholar
  37. 37.
    Landes BD, Petite JP, Flouvat B: Clinical pharmacokinetics of lansoprazole. Clin Pharmacokinet 1995, 28:458–470.PubMedCrossRefGoogle Scholar
  38. 38.
    Huber R, Hartmann M, Bliesath H, et al.: Pharmacokinetics of pantoprazole in man. Int J Clin Pharmacol Ther 1996, 34:185–194.PubMedGoogle Scholar
  39. 39.
    Gerloff J, Mignot A, Barth H, et al.: Pharmacokinetics and absolute bioavailability of lansoprazole. Eur J Clin Pharmacol 1996, 50:293–297.PubMedCrossRefGoogle Scholar
  40. 40.
    Klotz U: Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther 2006, 44:297–302.PubMedGoogle Scholar
  41. 41.
    Sjovall H, Bjornsson E, Holmberg J, et al.: Pharmacokinetic study of esomeprazole in patients with hepatic impairment. Eur J Gastroenterol Hepatol 2002, 14:491–496.PubMedCrossRefGoogle Scholar
  42. 42.
    Bell NJ, Burget D, Howden CW, et al.: Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 1992, 51(Suppl 1):59–67.PubMedCrossRefGoogle Scholar
  43. 43.
    Pantoflickova D, Dorta G, Ravic M, et al.: Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors. Aliment Pharmacol Ther 2003, 17:1507–1514.PubMedCrossRefGoogle Scholar
  44. 44.
    Miner P Jr, Katz PO, Chen Y, et al.: Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003, 98:2616–2620.PubMedCrossRefGoogle Scholar
  45. 45.
    Kalaitzakis E, Bjornsson E: A review of esomeprazole in the treatment of gastroesophageal reflux disease (GERD). Ther Clin Risk Manag 2007, 3:653–663.PubMedGoogle Scholar
  46. 46.
    Blum RA, Shi H, Karol MD, et al.: The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion. Clin Ther 1997, 19:1013–1023.PubMedCrossRefGoogle Scholar
  47. 47.
    Tolman KG, Sanders SW, Buchi KN, et al.: The effects of oral doses of lansoprazole and omeprazole on gastric pH. J Clin Gastroenterol 1997, 24:65–70.PubMedCrossRefGoogle Scholar
  48. 48.
    Geus WP, Mulder PG, Nicolai JJ, et al.: Acid-inhibitory effects of omeprazole and lansoprazole in Helicobacter pylori-negative healthy subjects. Aliment Pharmacol Ther 1998, 12:329–335.PubMedCrossRefGoogle Scholar
  49. 49.
    Janczewska I, Sagar M, Sjostedt S, et al.: Comparison of the effect of lansoprazole and omeprazole on intragastric acidity and gastroesophageal reflux in patients with gastroesophageal reflux disease. Scand J Gastroenterol 1998, 33:1239–1243.PubMedCrossRefGoogle Scholar
  50. 50.
    Hartmann M, Theiss U, Huber R, et al.: Twenty-four-hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole. Aliment Pharmacol Ther 1996, 10:359–366.PubMedCrossRefGoogle Scholar
  51. 51.
    Galmiche JP, Bruley Des Varannes S, et al.: Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers. Aliment Pharmacol Ther 2004, 19:655–662.PubMedCrossRefGoogle Scholar
  52. 52.
    Hunt RH, Armstrong D, James C, et al.: Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers. Am J Gastroenterol 2005, 100:1949–1956.PubMedCrossRefGoogle Scholar
  53. 53.
    Castell DO, Richter JE, Robinson M, et al.: Efficacy and safety of lansoprazole in the treatment of erosive reflux esophagitis. The Lansoprazole Group. Am J Gastroenterol 1996, 91:1749–1757.PubMedGoogle Scholar
  54. 54.
    Mee AS, Rowley JL: Rapid symptom relief in reflux oesophagitis: a comparison of lansoprazole and omeprazole. Aliment Pharmacol Ther 1996, 10:757–763.PubMedCrossRefGoogle Scholar
  55. 55.
    Hatlebakk JG, Berstad A, Carling L, et al.: Lansoprazole versus omeprazole in short-term treatment of reflux oesophagitis. Results of a Scandinavian multicentre trial. Scand J Gastroenterol 1993, 28:224–228.PubMedCrossRefGoogle Scholar
  56. 56.
    Mulder CJ, Dekker W, Gerretsen M: Lansoprazole 30 mg versus omeprazole 40 mg in the treatment of reflux oesophagitis grade II, III and IVa (a Dutch multicentre trial). Dutch Study Group. Eur J Gastroenterol Hepatol 1996, 8:1101–1106.PubMedCrossRefGoogle Scholar
  57. 57.
    Dekkers CP, Beker JA, Thjodleifsson B, et al.: Double-blind comparison [correction of Double-blind, placebo-controlled comparison] of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. The European Rabeprazole Study Group. Aliment Pharmacol Ther 1999, 13:49–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Kahrilas PJ, Falk GW, Johnson DA, et al.: Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther 2000, 14:1249–1258.PubMedCrossRefGoogle Scholar
  59. 59.
    Richter JE, Kahrilas PJ, Johanson J, et al.: Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001, 96:656–665.PubMedCrossRefGoogle Scholar
  60. 60.
    Labenz J, Armstrong D, Lauritsen K, et al.: A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO study. Aliment Pharmacol Ther 2005, 21:739–746.PubMedCrossRefGoogle Scholar
  61. 61.
    Stedman CA, Barclay ML: Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 2000, 14:963–978.PubMedCrossRefGoogle Scholar
  62. 62.
    Scarpignato C, Pelosini I: Review article: the opportunities and benefits of extended acid suppression. Aliment Pharmacol Ther 2006, 23(Suppl 2):23–34.PubMedCrossRefGoogle Scholar
  63. 63.
    Katz PO, Castell DO, Chen Y, et al.: Intragastric acid suppression and pharmacokinetics of twice-daily esomeprazole: a randomized, three-way crossover study. Aliment Pharmacol Ther 2004, 20:399–406.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Membrane Biology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA

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