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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor available for clinical use as a single isomer. It demonstrates pharmacological and clinical benefits beyond those seen with the racemic omeprazole.

Esomeprazole has higher and more consistent bio-availability than omeprazole, which results in a greater area under the plasma concentration–time curve. It is the area under the plasma concentration–time curve of omeprazole and esomeprazole that determines how much of each reaches the parietal cell, and thus the control of gastric acid secretion that is achieved. Esomeprazole, like other proton pump inhibitors, has a high specificity for the acidic environment of the parietal cell, where it is accumulated, activated and covalently inhibits the proton pump. Proton pumps elsewhere in the body do not achieve the level of acidity needed for accumulation and activation.

Esomeprazole, 40 mg once daily, provides more effective control of gastric acid secretion than omeprazole, 20 or 40 mg once daily, and all other proton pump inhibitors given at their standard doses. This translates into greater clinical effect compared with omeprazole, 20 mg once daily, and lansoprazole, 30 mg once daily, in the management of reflux disease. Esomeprazole therapy is well tolerated, with a low adverse events profile, similar to that seen with omeprazole.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

The development of omeprazole, the first proton pump inhibitor, marked a major step forward in the management of acid-related diseases. Earlier therapies that reduced acid secretion, such as anticholinergics, prostaglandin analogues and H2-receptor antagonists, acted via receptors on the basolateral membrane of the parietal cell. Thus, H2-receptor antagonists blocked histamine-driven acid secretion, but their action was compromised (at least in part) by the presence of alternative pathways for stimulation.1, 2 Furthermore, inter-individual variability in response to therapy with H2-receptor antagonists, the phenomenon of acid rebound and the development of tolerance were major drawbacks to the use of these drugs.3–6 H2-receptor antagonists were also relatively ineffective in the treatment of reflux oesophagitis.7, 8

In contrast, omeprazole acted in a direct way on the gastric H+,K+-ATPase (otherwise known as the proton pump) in the acid secretory canaliculus of the gastric parietal cell. This enzyme is the final common step of acid secretion, on which all stimulatory pathways converge.9 As a result of this direct action, omeprazole provided more reliable control of gastric acid secretion than the H2-receptor antagonists,10, 11 and thus faster symptom resolution and more predictable healing in gastro-oesophageal reflux disease and peptic ulcer disease.12 Omeprazole was followed by other proton pump inhibitors, namely lansoprazole, pantoprazole and rabeprazole, all with an identical general structure, consisting of a substituted pyridylmethylsulphinyl benzimidazole.

Although omeprazole provided more effective control of acid secretion than previous therapies, it was not equally effective in all patients. A study to investigate failed healing of severe oesophagitis by omeprazole in some patients showed that this was the result of inter-patient variability in responsiveness to therapy.13 There was therefore a need to find a therapy that provided even more effective control of acid secretion than that obtained with omeprazole, and which reduced the variation in acid inhibition between patients. After screening several hundred compounds, AstraZeneca found only four that progressed beyond pre-clinical studies and were tested in humans, and only one that exceeded omeprazole: its S-isomer, esomeprazole.14 This was a surprise, as it had been confirmed in 1990 that both isomers of omeprazole had the same inhibitory effect on the proton pump in an in vitro gastric gland model.15 However, at that stage, it had not been possible to prepare the single isomers in sufficient quantity for in vivo testing, and there appeared to be a slow racemization of the isolated isomers in aqueous solution.15 When both of the isomers could be produced in sufficient quantity to be studied in humans, it became apparent that the S-isomer was approximately four times more potent than the R-isomer after oral administration.16

Esomeprazole has a higher bio-availability than omeprazole

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

The superior clinical efficacy of esomeprazole, compared with omeprazole and the R-isomer, is the result of a higher systemic bio-availability. Studies in human liver microsomes have shown that there is a significant stereoselectivity in the metabolism of the optical isomers of omeprazole to the main metabolites, omeprazole sulphone, 5-hydroxy- and 5-O-desmethyl omeprazole, which are all inactive.17 The metabolism of the two isomers is mediated primarily by the two hepatic cytochrome P450 isoforms, CYP2C19 and CYP3A4, but the ratios in which they are metabolized by the two enzymes differ. Esomeprazole is metabolized to a greater extent than the R-isomer by CYP3A4 and, to a lesser extent, by CYP2C19. The intrinsic clearance of esomeprazole (the S-isomer) is approximately three times lower than that of the R-form. This is mainly explained by the considerably lower intrinsic clearance of esomeprazole through CYP2C19 to the 5-hydroxy metabolite, compared with the R-isomer (Figure 1). The first-pass metabolism of esomeprazole is therefore decreased compared with that of the R-isomer and omeprazole, and the total metabolic clearance of esomeprazole is lower than that of the R-isomer, resulting in higher plasma levels.

image

Figure 1. Metabolic scheme illustrating the intrinsic clearance values (CLint) for the different metabolic pathways of esomeprazole and R-omeprazole from in vitro experiments on human liver microsomes. Values of CLint are expressed as µL/mL per milligram of protein. (From Andersson et al.16 with permission.)

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This advantageous metabolism of esomeprazole results in a greater area under the plasma concentration–time curve (AUC) than that obtained for omeprazole or the R-isomer at the same oral dose.18–20 Thus, in an early pharmacokinetic cross-over study of 15-mg doses of esomeprazole, the R-isomer and omeprazole in healthy volunteers, the mean AUC for esomeprazole was four times that of the R-isomer and almost twice that of omeprazole on day 7.18 Similarly, esomeprazole, 20 mg once daily for 5 days, resulted in an AUC approximately 70% higher than that obtained with omeprazole at the same dose.19 In patients with gastro-oesophageal reflux disease, the AUC value for esomeprazole, 40 mg once daily, was five times that of omeprazole, 20 mg once daily, after 5 days of treatment, and a comparison of 20-mg doses of the two drugs showed an 80% higher AUC with esomeprazole on day 5.20 In addition, the variability between patients in AUC (as demonstrated by the standard deviation of the log AUC values) was less with esomeprazole 40 mg (0.47) than with esomeprazole 20 mg (0.64) or omeprazole 20 mg (0.73).20 This greater consistency of the pharmacokinetics of esomeprazole, compared with omeprazole, was matched by a reduced inter-patient variability in the percentage of time for which the intragastric acidity exceeded pH 4.20 Thus, the higher and more consistent bio-availability of esomeprazole provides the rationale for its superior control of gastric acid secretion and improved clinical efficacy compared with omeprazole.

A specific action on the proton pump

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

Like omeprazole and the other proton pump inhibitors, esomeprazole is a pro-drug, which must be converted in the parietal cell to its active chemical form (for a review of the mechanism of action of omeprazole, and hence esomeprazole, see Lindberg et al.21). It is a lipophilic weak base, is inactive at neutral pH, circulates in the blood and can cross biological membranes. When acid is being secreted, the pH value within the secretory canaliculi of the gastric parietal cells is pH 1. As esomeprazole has a pKa value of about four, it passes freely into the canaliculus and, because of the high acidity, becomes protonated. In the protonated form, it is membrane-impermeable and thus starts to accumulate as a consequence of the proton gradient between the parietal cell cytoplasm (pH 7.3) and the canaliculus (pH 1). This results in a concentration of esomeprazole in the canaliculus that theoretically could be 1000-fold greater than its level in the blood and other tissues. At pH 1, esomeprazole is rapidly converted to the sulphenamide, which is the active inhibitor of the H+,K+-ATPase (the proton pump). Inhibition of the proton pump is achieved through binding of the reactive sulphur atom on the sulphenamide to the thiol groups of cysteine amino acids on the luminal surface of the enzyme, forming an inactive covalent complex.9

The specificity of the inhibition has been confirmed experimentally using 14C-radiolabelled omeprazole in the mouse.22 One minute after intravenous administration of omeprazole, 15 µmol/kg, radiolabel was detected primarily in the stomach, liver, lungs and kidneys; after 5 min, it was located mainly in the stomach and liver; after 16 h, the radiolabel was confined to the gastric wall. Closer examination at this stage showed that virtually all of the radiolabel was located in the parietal cells, where it was confined to the tubulo-vesicles and secretory vesicles, the site of the proton pump. Biochemical analyses further identified the catalytic subunit of the proton pump as the protein that binds the drug.23

Although the plasma half-life of proton pump inhibitors in humans is fairly short (about 60 min for omeprazole), their duration of action is much longer, and some antisecretory effect is still present 24–72 h after a dose.24 Their specific mechanism of action leads to unique pharmacodynamics: as the proton pump inhibitor binds covalently to the proton pump, the total delivery of the drug to the active pump is more important than the concentration of the drug at a specific time point (the peak concentration).24, 25 It is the AUC value of omeprazole and esomeprazole that determines how much of each proton pump inhibitor reaches the parietal cell, and is therefore a major factor in determining the control of gastric acid secretion achieved.16, 24 Once within the parietal cell, the two enantiomers of omeprazole are equipotent inhibitors of the proton pump. However, the advantageous metabolism of esomeprazole, which results in higher AUC values than for omeprazole at the same dose, translates into superior control of gastric acid secretion.

Superior acid control compared with all other proton pump inhibitors

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

The inhibition of pentagastrin-stimulated acid secretion by esomeprazole in healthy volunteers after 1 and 5 days of therapy has been shown to be dose-dependent, with an increased effect on repeated dosing.19 Furthermore, the antisecretory effect can be correlated with the AUC value (Figure 2). The inhibition of pentagastrin-stimulated acid secretion with esomeprazole, 20 mg once daily, was 31% greater than that with omeprazole, 20 mg once daily, on the first day of therapy, and remained 13% higher after 5 days.

image

Figure 2. Percentage acid inhibition with esomeprazole is correlated with the area under the plasma concentration–time curve (AUC). The graph shows day 5 data, and the line represents the predicted acid inhibition (from Andersson et al.19). [Reprinted with permission from Blackwell Science (Aliment Pharmacol Ther 2001; 15: 1563–9).]

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In addition, a number of studies in healthy volunteers and patients with gastro-oesophageal reflux disease have compared the efficacy of esomeprazole and the other proton pump inhibitors in maintaining an intragastric pH > 4 (this value being chosen because it is the critical threshold of acid control for the effective management of gastro-oesophageal reflux disease).10 Esomeprazole, 40 mg once daily, maintained an intragastric pH > 4 for significantly longer during the subsequent 24-h period than did standard doses of lansoprazole, pantoprazole and rabeprazole, and these differences became apparent from the first day of dosing (Figure 3).26–28 Furthermore, esomeprazole, 40 mg once daily, was superior to both omeprazole, 20 mg once daily,20 and omeprazole, 40 mg once daily (double the standard dose),29 in this regard, and esomeprazole, 20 mg once daily, was superior to omeprazole, 20 mg once daily.20 This provides further evidence that the higher AUC achieved with esomeprazole, compared with the same dose of omeprazole, results in improved inhibition of the proton pump.

image

Figure 3. Esomeprazole, 40 mg once daily, controlled the intragastric pH > 4 for longer than omeprazole, 20 or 40 mg once daily, lansoprazole, 30 mg once daily, pantoprazole, 40 mg once daily, and rabeprazole, 20 mg once daily. The graphs show day 5 data.20, 26–29

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On the basis of this evidence, the different proton pump inhibitors do not, as has been suggested by Kromer et al., ‘display similar dose–response relationships with similar potencies and efficacies on a milligram basis.’30 The superior acid control achieved with the chosen standard dose of esomeprazole, 40 mg once daily, compared with omeprazole, 20 mg once daily, and lansoprazole, 30 mg once daily, has been shown to translate into greater clinical efficacy in patients with gastro-oesophageal reflux disease. Thus, erosive oesophagitis was healed at week 8 in significantly more patients who were treated with esomeprazole, 40 mg once daily, compared with those treated with omeprazole, 20 mg once daily.31, 32 Indeed, in one study, the healing rate achieved at 4 weeks with esomeprazole (81.7%) was close to that achieved at 8 weeks with omeprazole (84.2%). After 8 weeks of esomeprazole therapy, 93.7% of patients were healed (P < 0.001 vs. omeprazole).32 Moreover, esomeprazole, 40 mg once daily, provided the sustained resolution of heartburn more rapidly and in significantly more patients than did omeprazole, 20 mg once daily.31, 32

Similarly, esomeprazole, 40 mg once daily, was significantly more effective than lansoprazole, 30 mg once daily, in the healing of reflux oesophagitis at 4 and 8 weeks, and sustained resolution of heartburn occurred faster and in more patients treated with esomeprazole.33 Esomeprazole, 20 mg once daily, has also been shown to be highly effective when given as maintenance therapy for healed oesophagitis,34, 35 and is significantly superior to lansoprazole, 15 mg once daily, in maintaining remission across all pre-treatment grades of oesophagitis.36

Selectivity of esomeprazole

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

The clinical efficacy of esomeprazole reflects its advantageous metabolism compared with omeprazole, which results in improved delivery to the parietal cell. Like all proton pump inhibitors, esomeprazole has a high specificity for the acidic canalicular space of the parietal cell, where it inhibits the gastric H+,K+-ATPase. Although similar (but not identical) H+,K+-ATPases exist in the colon and kidney, the acidity in these regions does not reach the level necessary for proton pump inhibitor accumulation and transformation to the active sulphenamide. In vivo experiments in acid-loaded rats with induced levels of renal H+,K+-ATPase therefore failed to show any effect of high intravenous doses of omeprazole on the urinary excretion of potassium or hydrogen ions.37

There has, however, been some speculation that proton pump inhibitors may interfere with lysosomal function by reacting with vacuolar H+-ATPases (V-ATPases). These enzymes are found in a number of locations in the body, including lysosomes, endosomes, chromaffin granules and the acidic hemivacuole of osteoclasts, and generate pH values of 4.5–6.5.38 Indeed, Kromer et al. have suggested that omeprazole carries a greater potential risk than pantoprazole of causing adverse events due to effects in moderately acidic compartments in the body.30, 39, 40 They claim that the ratio of the serum elimination half-life to the chemical activation half-life at ‘a critical pH of about 5’ is important in determining the exposure of moderately acidic tissues to the activated proton pump inhibitor. No explanation is provided as to why pH ≈ 5 is critical, and the ratio is of questionable meaning. As explained earlier, it has been shown for omeprazole and esomeprazole that the AUC value is the key factor in determining how much proton pump inhibitor reaches any potential target tissue, and the degree of acidity within that tissue will determine the extent of any accumulation of the proton pump inhibitor. Many of the arguments presented by Kromer et al. in support of their hypothesis are flawed, and are addressed in the following paragraphs, using available data on omeprazole as representative of the proton pump inhibitor class.

The pKa values of the proton pump inhibitors restrict accumulation of the compounds to acid spaces, such as the parietal cell. The pKa values of esomeprazole, omeprazole, pantoprazole and lansoprazole are similar, pKa ≈ 4, thus allowing all of these agents to accumulate about 1000-fold in the parietal cell at pH 1.41 Once within the parietal cell, the rate of onset of inhibition of the proton pump will be affected by the rate of activation of the proton pump inhibitor. At the pH of the lysosome, pH ≈ 5, no accumulation of the protonated form of esomeprazole can occur. Even rabeprazole, which is most prone to accumulate (due to its higher pKa value of ≈ 5), will show little accumulation at all but the most acidic lysosomal pH values. Moreover, any molecules that are activated to the sulphenamide at neutral pH (a process that occurs some 600-fold more slowly than in the stomach, and 600 000-fold more slowly if one includes an accumulation factor of 1000) will be scavenged by thiols, such as cysteine and glutathione, resulting in the formation of the sulphide of the proton pump inhibitor. In the case of omeprazole, the majority of the sulphide formed is then converted back to omeprazole in the liver. Glutathione is found in high concentrations in eukaryotic cells (2–10 mmol/L),42 and in the blood (about 1 mmol/L),43 and plays a vital role in maintaining a reduced environment in the body.

The in vitro experiments conducted by Kromer et al., which purport to show that omeprazole displays a greater liability than pantoprazole to inhibit renal Na+,K+-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils, have a number of flaws.40 These relate to the use of non-physiological conditions and proton pump inhibitor concentrations of up to 100 µm, which are approximately 1000-fold higher than that in plasma. The peak plasma concentration of omeprazole is reported to be 2.5 µm (range, 1–5 µm) after a 40-mg dose,44 and more than 95% is protein bound.25 Thus, 0.1 µm is the maximum free concentration of omeprazole in the blood and, probably, in the lysosome. Furthermore, the use by Kromer et al. of a freeze-dried preparation of the gastric H+,K+-ATPase is likely to have destroyed the integrity of the canalicular membrane, making both sides of the protein equally accessible.40 Most of the inhibition observed in this situation is likely to be due to a reaction between the activated form of the proton pump inhibitor and free sulphydryl groups on the larger, cytosolic face of the protein. This is irrelevant to the situation in vivo, where the enzyme is sited in the cell membrane and low-molecular-weight thiols, such as glutathione, in the cell would protect the cytosolic face. Indeed, early experiments with omeprazole showed a similar, non-specific action between omeprazole and the gastric H+,K+-ATPase under non-physiological conditions.45 However, when physiological conditions were mimicked in vitro, a specific reaction occurred purely on the extracellular side of the membrane.

The inhibition of lysosomal acidification by omeprazole, cited by Kromer et al.,40 was also observed under non-physiological conditions, in which the cytosolic face of the lysosomal V-ATPase was exposed to proton pump inhibitor in the absence of protective thiols.46 Others have similarly reported an inhibitory effect of omeprazole at high concentrations (> 100 µm) on, for example, lysosomal V-ATPase in kidney- and bone-derived membrane vesicles.47 However, in all of these cases, this inhibitory effect could be abolished by exogenous glutathione (which cannot pass through membranes), indicating that omeprazole was interacting with cytosolic rather than luminal SH-groups on the V-ATPase. Unlike the gastric proton pump, the lysosomal enzyme (which belongs to a structurally dissimilar family of enzymes) does not seem to have critical SH-groups at sites facing the acid space, and lysosomal acidification is therefore unlikely to be inhibited in vivo. When given in doses that inhibited gastric acid secretion in rats, omeprazole had no observable effect on hepatic lysosomal integrity, lysosomal enzyme activity or biliary lysosomal enzyme secretion.48

These data all serve to highlight the hazards involved in attempting to transfer in vitro findings to the in vivo situation and, in particular, in not taking the normal physiological conditions into account. The greater ‘potential risk’ of omeprazole therapy relative to pantoprazole, suggested by Kromer et al., based on non-physiological in vitro experiments, is of questionable relevance in a clinical setting, where the safety record of these proton pump inhibitors speaks for itself.

Omeprazole and esomeprazole have a very good safety profile

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

An accumulated total of more than 600 million patient treatments with omeprazole (as of 1 January 2002) have provided no cause for concern about safety (AstraZeneca, data on file). In accordance with this, esomeprazole, after 36 million patient treatments (by September 2002) so far, has a very similar safety profile to omeprazole. Documentation of the long-term safety of esomeprazole comes from two 6-month maintenance studies in reflux oesophagitis and a 12-month open-label study with esomeprazole, 40 mg once daily.34, 35, 49 As might be expected, these showed that the adverse event profile for esomeprazole is low, similar to that of omeprazole.

Extensive clinical experience has shown omeprazole to have a good safety profile and to be well tolerated.50–52 Indeed, the good long-term tolerability of omeprazole has been documented in patients with gastro-oesophageal reflux disease taking maintenance therapy for up to 11 years,53 and in patients with Zollinger–Ellison syndrome who have been treated for up to 9 years with high doses of omeprazole, receiving up to 480 mg daily at times.54, 55 Furthermore, a 5-year follow-up of a study comparing the benefits of anti-reflux surgery with omeprazole therapy found no significant difference between the two groups with regard to serum electrolytes, blood and liver status and serum values of vitamin B12.56

A comparison of the common adverse events reported during treatment with proton pump inhibitors in general practice in England showed that they were infrequent and that there were only small absolute differences in event rates between omeprazole, lansoprazole and pantoprazole.57 The most common adverse events were diarrhoea, nausea/vomiting, abdominal pain and headache. Compared with omeprazole, pantoprazole was associated with significantly higher rates of myalgia and headache, and lansoprazole with significantly higher rates of diarrhoea (particularly amongst older patients), depression, headache, malaise, myalgia and nausea/vomiting.

Although the identification of uncommon or idiosyncratic adverse events requires follow-up in very large numbers of patients, product surveillance programmes have not identified any serious consequences related to the use of omeprazole.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References

Esomeprazole is the first single-isomer proton pump inhibitor. It has higher bio-availability than omeprazole, and provides more pronounced inhibition of acid secretion compared with all other clinically available proton pump inhibitors. This translates into clinical superiority, as has been explicitly documented for efficacy relative to omeprazole and lansoprazole, and for predictability of response relative to omeprazole.

Omeprazole has high specificity for the parietal cell, and accumulated experience with this proton pump inhibitor has provided no cause for concern regarding its safety. As expected, esomeprazole has so far shown a similar safety profile.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Esomeprazole has a higher bio-availability than omeprazole
  5. A specific action on the proton pump
  6. Superior acid control compared with all other proton pump inhibitors
  7. Selectivity of esomeprazole
  8. Omeprazole and esomeprazole have a very good safety profile
  9. Conclusions
  10. References
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