Clin Pharmacokinet 2008; 47 (1): 1-6

LEADING ARTICLE 0312-5963/08/0001-0001/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Proton Pump Inhibitors

Do Differences in Pharmacokinetics Translate into Differences in
Clinical Outcomes?
Kwong Ming Fock,1 Tiing Leong Ang,1 Lean Choo Bee2 and Edmund Jon Deon Lee2
1 Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore
2 Department of Pharmacology, National University of Singapore, Singapore

Abstract Acid-related disorders are common management problems in clinical practice. The key to effective manage-
ment is successful suppression of gastric acid production. Proton pump inhibitors (PPIs) are the most potent acid
suppressants available and are significantly more effective than histamine H2 receptor antagonists. Although
PPIs are highly effective as a class, differences in their pharmacokinetics, such as bioavailability, elimination
half-life and metabolism, may translate into differences in clinical outcomes. A new immediate-release
omeprazole has been introduced, which allows rapid absorption. This has been shown to produce significantly
better nocturnal gastric acid control than delayed-release tablets. The bioavailability of rabeprazole on day 1 is
greater than with other PPIs, and this may translate into faster onset of symptom relief for patients with gastro-
oesophageal reflux disease. On the other hand, the bioavailability of esomeprazole increases 3-fold at day 5, and
it has been shown that on day 5, esomeprazole provided significantly more effective control of gastric acid than
other PPIs. The exact clinical significance of these observations remains to be determined. There is genetic
polymorphism in PPI metabolism via cytochrome P450 2C19. In Helicobacter pylori eradication, a significantly
lower eradication rate was seen in extensive metabolisers with omeprazole and lansoprazole but not with
rabeprazole. The oesophagitis healing rate was lower in extensive metabolisers with lansoprazole but not with
rabeprazole. The currently available PPIs have short elimination half-lives ranging from 1 to 1.5 hours.
Tenatoprazole is a new PPI that has a 5- to 7-fold longer elimination half-life than current PPIs. It could be
potentially more useful for the treatment of gastro-esophageal reflux disease and nocturnal acid breakthrough
than other PPIs.

Acid-related disorders are common management problems in ate H+ ions. Histamine is the principal paracrine transmitter,
clinical practice. These disorders include gastro-oesophageal re- exerting its effects by binding histamine H2 receptors on parietal
flux disease (GORD), peptic ulcer disease and stress-related ero- cells. Gastrin, which is secreted by antral G cells, comprises the
sive syndrome. The key to effective management of these acid- endocrine pathway; it exerts its effects directly and indirectly by
related disorders is successful suppression of gastric acid produc- stimulating the release of histamine by enterochromaffin-like cells
tion. For instance, maintenance of intragastric pH at >3 has been of the gastric corpus and fundus. Regardless of the initial pathway
correlated with healing of duodenal ulcers,[1] and maintenance of of gastric acid stimulation, the gastric enzyme H+,K+-adenosine
intragastric pH at >4 has been correlated with healing of gastric triphosphatase (ATPase) constitutes the final step of acid secre-
ulcers[2] and erosive oesophagitis.[3] In the context of bleeding tion.
peptic ulcers, maintenance of intragastric pH at >6 appeared Medications that are commonly used to treat acid-related disor-
optimal in preventing rebleeding by facilitating clot formation and ders include antacids, H2-receptor antagonists (H2RAs) and proton
prevention of clot lysis.[4] pump inhibitors (PPIs). Antacids work by simply neutralising
The generation of H+ ions by the parietal cells of the gastric gastric acid rather than by suppressing its secretion. H2RAs sup-
mucosa is mediated by three pathways: neurocrine, paracrine and press gastric acid secretion by competitively and reversibly block-
endocrine (figure 1). Acetylcholine, which is released by vagal ing the H2 receptor on the gastric parietal cell. On the other hand,
postganglionic neurons, is the principal neurocrine transmitter, PPIs work by undergoing acid-catalysed conversion to reactive
stimulating the muscarinic M3 receptors on parietal cells to gener- species, which are permanent cations. These reactive species then
2 Fock et al.

ECL cells practice; other PPIs that were subsequently introduced include
Gastrin secrete
histamine lansoprazole, pantoprazole, rabeprazole and esomeprazole. Te-
Acetycholine binds to
muscarinic receptors
natoprazole, a new PPI that has been developed, has an imidazopy-
Histamine binds to
ridine ring in place of the benzimidazole ring. PPIs are prodrugs
H2 receptors: and formulated as delayed-release enteric-coated preparations.
inhibited by H2RAs The enteric coating protects against premature acid degradation in
Gastric parietal cell
the stomach so that absorption can occur in the proximal small
intestine.
The pharmacokinetics of currently available PPIs, based on
H+,-K+-ATPase: information available from the product monographs, are sum-
inhibited by PPIs marised and shown in table I. The absolute bioavailability ranges
Fig. 1. The generation of H+ ions by the parietal cells of the gastric mucosa from 35% for a single dose of omeprazole to 89% with repeat
is mediated by three pathways: acetylcholine stimulates the muscarinic M3 administration of esomeprazole. Unlike other PPIs, the bioavaila-
receptors; histamine exerts its effects by binding to histamine H2 receptors; bility of rabeprazole remains unchanged with repeat dosing. On
and gastrin exerts its effects directly and indirectly by stimulating the re-
the whole, the time to reach the peak plasma concentration (tmax)
lease of histamine by enterochromaffin-like (ECL) cells of the gastric
corpus and fundus. The gastric enzyme H+,K+- adenosine triphosphatase is about 2 hours. After absorption into the circulation, PPIs are
(ATPase) constitutes the final step of acid secretion. H2RAs = H2 receptor taken up preferentially by gastric parietal cells, especially when
antagonists; PPIs = proton pump inhibitors. they are actively secreting acid. Within the acidic environment of
the parietal cells, PPIs undergo protonation of the pyridine moiety,
bind covalently to H+,K+-ATPase, causing irreversible inhibition making them less membrane permeable and leading to accumula-
of the final step in gastric acid secretion. PPIs are the most potent tion within the parietal cells. PPIs then undergo a second protona-
gastric acid suppressants and have been shown to be much more tion on the benzimidazole or imidazopyridine ring, forming a
effective than H2RAs in the management of GORD[3,5,6] and peptic sulfenamide derivative, which is the active form of the drug that
ulcer disease.[7,8] binds covalently to cysteine moieties of the membrane-bound
Although PPIs are highly effective as a class, there are differ- H+,K+-ATPase molecule, thus inhibiting gastric acid secretion.
ences in pharmacokinetics, such as bioavailability, elimination Once inhibition occurs, recovery can only occur with regeneration
half-life and metabolism between individual PPIs, and these dif- or resynthesis of new ATPase. Recovery is therefore generally a
ferences may translate into differences in clinical outcomes. This relatively slow process compared with the initial inactivation.
review critically examines the relationship between these pharma- These mechanisms suggest that the kinetics of the recovery from
cokinetic differences and clinical outcome data. The literature PPI effects may not be critically dependent on the circulating
search included MEDLINE and manual searches of bibliographies plasma concentrations of PPIs and that, despite the short elimina-
of key articles related to the pharmacokinetics of PPI and the tion half-lives, the biological effect persists for much longer. All
impact on clinical outcomes published in English up to January PPIs are extensively protein bound and undergo hepatic metabol-
2007. ism via the cytochrome P450 (CYP) pathways.
The true potencies of PPIs are difficult to establish. In vivo
1. Pharmacokinetics of Proton Pump Inhibitors studies are complicated by interspecies differences in the distribu-
(PPIs): Similarities and Differences tion and kinetics of the different PPIs. In vitro studies may be free
of pharmacokinetic differences but are still affected by interspe-
The current PPIs are benzimidazole derivatives with a pyridine cies and intertissue differences. Since the activation of PPIs is
moiety. Omeprazole was the first PPI introduced into clinical dependent on the pH, apparent differences in the rank order of the

Table I. Pharmacokinetics of proton pump inhibitors (PPIs)

PPI [dose (mg)] tmax (h) Bioavailability Protein t1/2 (h) Hepatic Reference
(%) binding (%) metabolism
Esomeprazole (20) 1–2 64–89 97 1.3 Yes 9
Lansoprazole (30) 1.7 >80 97 1.5 Yes 10
Omeprazole (20) 2 35–60 95 0.5–1 Yes 11
Pantoprazole (20) 2.5 77 97 1 Yes 12
Rabeprazole (20) 3.5 52 97 1 Yes 13
t1/2 = elimination half-life; tmax = time to reach peak plasma concentration.

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (1)
PPIs: Differences in PK and Clinical Outcomes 3

potency of the various PPIs, even in isolated gastric glands, may 2. Clinical Impact of Pharmacokinetic Differences
be confounded by the pH of the incubation media. In a study using Between PPIs
isolated gastric glands of mongrel rabbits at a pH of 7.4, five PPIs
As a class, all PPIs are very effective in the treatment of acid-
were ranked in the following order of potency: lansoprazole >
related disorders. Omeprazole, esomeprazole, pantoprazole, lan-
omeprazole > rabeprazole > RO-18-5364 > pantoprazole.[14] How-
soprazole and rabeprazole largely exhibit clinical equivalence over
ever, despite rankings like these, all PPIs are very potent in their the full course of therapy for acid-related disorders. However,
ability to inhibit H+,K+-ATPase and can produce maximum inhi- differences in their pharmacokinetics have been observed, and
bition at appropriate doses. At the studied doses, not all PPIs these may translate into treatment advantages in specific clinical
produce total inhibition over 24 hours when administered as a situations.
single dose. There is a decline in inhibition, which is determined
by regeneration of activity resulting from breakdown of the cova- 2.1 Absorption and Bioavailability
lent binding as well as formation of new ATPases. The estimated
half-lives of recovery of acid secretion range from 15 hours for The current PPIs are delayed-release enteric-coated prepara-
tions. The enteric coating protects against premature acid degrada-
lansoprazole to 28 hours for omeprazole and 46 hours for panto-
tion in the stomach but delays absorption, thus delaying the onset
prazole. Theoretically, however, maximum inhibition over 24
of action. The recently introduced immediate-release omeprazole
hours may be achievable if appropriately high doses are used.[15] consists of pure, non-enteric-coated omeprazole powder along
Differences in pharmacokinetics may affect clinical outcomes. with sodium bicarbonate, which is constituted with water to be
As mentioned earlier, the current PPIs are delayed-release enteric- drunk. The sodium bicarbonate powder protects against acid deg-
coated preparations. Recently, a new immediate-release omepra- radation in the stomach, whereas the absence of an enteric coat-
zole (Zegerid®)1 has been introduced. It consists of pure, non- ing facilitates rapid absorption. Immediate-release omeprazole has
enteric-coated omeprazole powder along with sodium bicarbonate, been shown to display a significantly shorter tmax (25 minutes vs
which acts as a buffer against gastric acid degradation. The ab- 127 minutes) and a higher maximum plasma concentration (Cmax;
sence of an enteric coating facilitates rapid absorption. PPIs under- 1019 ng/mL vs 544 ng/mL) when compared with omeprazole.
Despite the more rapid onset of anti-secretory action, there is no
go hepatic metabolism via the CYP system and the isoforms
shortening of the duration of effect.[19] Castell et al.[20] compared
CYP2C19 and CYP3A4 in particular. Esomeprazole is the S-
immediate-release omeprazole with pantoprazole in the manage-
isomer of omeprazole, which is a racemic mixture of two optical ment of nocturnal acid breakthrough (NAB). Repeated once-daily
isomers, the R- and S-isomers. Esomeprazole and the R-isomer (bedtime) dosing with immediate-release omeprazole produced
differ in the ratios in which they are metabolised by CYP2C19 and significantly better nocturnal gastric acid control than repeated
CYP3A4. In vitro experiments using human liver microsomes once daily (pre-dinner) or twice-daily dosing with delayed-release
have shown that esomeprazole is metabolised to a greater extent pantoprazole (median pH 4.7 vs 2.0 and 1.7; percentage of time
by CYP3A4 than the R-isomer (and hence omeprazole at the same when the pH was >4, 55% vs 27% and 34%; NAB 53% vs 78%
dose) and to a lesser extent by CYP2C19.[16] Esomeprazole has a and 75%, respectively). Twice-daily dosing (pre-breakfast and at
lower total intrinsic clearance than omeprazole and the R-isomer, bedtime) with immediate-release omeprazole 20 mg and 40 mg
and its first-pass metabolism is decreased compared with achieved the best nocturnal control of gastric acidity.
omeprazole. The advantageous metabolism of esomeprazole re- Among the different types of delayed-release PPI, there are
sults in higher area under the plasma concentration-time curve differences in relative bioavailability after single and repeated
dosing. Rabeprazole, lansoprazole and pantoprazole have similar
(AUC) values than those for omeprazole at the same dose, and
bioavailability on days 1 and 5. The bioavailability of omeprazole
hence may achieve better acid suppression than omeprazole in
increases 1.5- to 2-fold at day 5, while that of esomeprazole
clinical practice.[16,17] Genetic polymorphisms in CYP2C19 exist
increases 3-fold at day 5.[21] It is still not clear whether these
and may affect the metabolism of individual PPIs to different differences between delayed-release PPIs are really clinically im-
extents, thereby influencing clinical outcomes.[18] The newly de- portant. Inhibition of gastric acid secretion following single-dose
veloped imidazopyridine-based PPI tenatoprazole has an elimina- administration depends on the concentrations of the PPI that are
tion half-life of 7 hours, which is considerably longer than that of achieved. It may therefore be expected to be related to the adminis-
the current benzimidazole-based PPIs. A longer duration of action tered dose and bioavailability. Comparisons between PPIs are
is potentially advantageous, especially for nocturnal acid control. difficult, as this will depend on the administered dose relative to its

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (1)
4 Fock et al.

potency in inhibiting H+,K+-ATPase. Most clinical reports com- the patient’s global evaluation. When the pretreatment and post-
pare clinically used doses rather than pharmacologically equiva- treatment symptom severity scores for each PPI were compared,
lent doses and therefore do not give a true picture of any potential rabeprazole significantly reduced daytime and nocturnal heartburn
differences in clinical efficacy. However, as the presence of PPIs scores within 2 days of commencing treatment, while for patients
in the circulation, and presumably at the gastric mucosa, is usually receiving esomeprazole, a statistically significant improvement in
in excess of the time needed for their activation, differences in the daytime heartburn score was seen only from days 3 to 5, and no
activation rates may not actually be that important in determining significant improvement in the nocturnal heartburn score was seen
the extent of inhibition.[21] In contrast, it has been suggested that in the first 5 days.
slow activation of PPIs such as pantoprazole and tenatoprazole
may allow these PPIs to access and bind to the deeper cysteine-822 2.2 Cytochrome P450 2C19 Polymorphisms
residue. Inactivation through this deeper residue may in fact be and Metabolism
more resistant to reactivation of ATPases by endogenous reducing
All PPIs undergo hepatic biotransformation via the hepatic
agents. Inhibition of gastric acid secretion following multiple
CYP2C isoforms.[18] The relative impact of the CYP2C19 pathway
doses is cumulative, and achievement of a steady-state levels of
on metabolism of PPIs has been reported to be omeprazole =
gastric acid inhibition may be anticipated, depending on the half-
esomeprazole > pantoprazole > lansoprazole > rabeprazole.
life of recovery for that particular PPI. Typically, maximum inhi-
CYP2C19 genotypes are classified into the three groups: extensive
bition may be expected to occur after at least a few days of therapy.
metabolisers (EMs), intermediate metabolisers (IMs) and poor
Pantoflickova et al.[22] compared the degree of acid inhibition metabolisers (PMs).[26] The metabolism of rabeprazole does not
of single doses of rabeprazole, lansoprazole, pantoprazole, appear to be significantly affected by CYP2C19 polymorphism,
omeprazole capsules and the omeprazole multiple-unit pellet sys- whereas for omeprazole, lansoprazole and pantoprazole, a marked
tem (MUPS) tablet in a crossover, double-blind, randomised study difference in metabolism exists between EMs and PMs.[18] These
performed in 18 Helicobacter pylori-negative subjects. The intra- differences in polymorphisms affect the metabolic and pharmaco-
gastric pH and the percentage of time when the pH was >4 during kinetic profiles of PPIs and may influence the therapeutic effec-
the 24-hour post-dose period were significantly higher with tiveness. At the same time, the effect of H2RA co-therapy in
rabeprazole than with the other PPIs. In addition, both the daytime CYP2C19 polymorphisms has been studied. Furuta et al.[27] exam-
and nocturnal pH values were higher with rabeprazole and lan- ined the effect of twice-daily famotidine on gastric acid inhibition
soprazole than with pantoprazole, omeprazole capsules and in 20 healthy volunteers who took lansoprazole twice daily. It was
omeprazole MUPS tablets. Lind et al.[23] compared esomeprazole found that although the intragastric pH was significantly higher in
20 mg and 40 mg with omeprazole 20 mg once daily in terms of PMs taking lansoprazole twice daily than in rapid metabolisers,
the percentage of time when the pH was >4 at day 5 in patients this influence was offset by concomitant use of famotidine. This
with GORD. It was found that on day 5 of treatment, esomeprazole suggested that H2RA may be a useful co-therapy in the context of
40 mg or 20 mg once daily maintained intragastric pH at >4 for inadequate acid suppression due to CYP2C19 polymorphisms.
16.8 and 12.7 hours, respectively, compared with 10.5 hours for Kawamura et al.[28] demonstrated that the therapeutic effect of
omeprazole 20 mg once daily. Miner et al.[24] conducted a random- lansoprazole on erosive oesophagitis was influenced by the
ised, open-label, comparative, five-way crossover study that eval- CYP2C19 genotype status. At 4 weeks, the healing rates were
uated the 24-hour intragastric pH profile at day 5 of oral es- 57.1%, 69.2% and 72.7% in EMs, IMs and PMs, respectively,
omeprazole, lansoprazole, omeprazole, pantoprazole and rabepra- while the healing rates at 8 weeks were 77.4%, 95.0% and 100%,
zole in 34 H. pylori-negative patients with symptoms of GORD. respectively. The healing rate of erosive reflux oesophagitis was
On day 5, esomeprazole at the standard dose of 40 mg once daily significantly lower in EMs than in the other two groups. Converse-
provided significantly more effective control of gastric acid than ly, Ariizumi et al.[29] showed that in the case of rabeprazole,
other PPIs at standard doses. The intragastric pH was maintained similar healing rates at 4 and 8 weeks were obtained in EMs, IMs
at >4 for a mean period of 14.0 hours with esomeprazole, and PMs.
12.1 hours with rabeprazole, 11.8 hours with omeprazole, Sevaral studies have also demonstrated the impact of CYP2C19
11.5 hours with lansoprazole and 10.1 hours with pantoprazole. polymorphism in the context of H. pylori eradication.[30-40] Furuta
Fock et al.[25] evaluated the efficacy and safety of rabeprazole et al.[30] investigated whether CYP2C19 genotype status was asso-
versus esomeprazole in relieving symptoms in patients with non- ciated with different cure rates for H. pylori infection and peptic
erosive reflux disease. After 4 weeks of treatment, rabeprazole ulcers, using dual therapy with omeprazole and amoxicillin. The
10 mg and esomeprazole 20 mg were comparable with regard to cure rates for H. pylori infection were 28.6%, 60% and 100% in
the primary endpoint of the time taken to achieve a 24-hour the EM, IM and PM groups, respectively. CYP2C19 polymor-
symptom-free interval and were similarly efficacious in term of phism was also shown to be a major predictor of treatment failure

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (1)
PPIs: Differences in PK and Clinical Outcomes 5

in White patients when lansoprazole-based quadruple therapy was three-period crossover study. Tenatoprazole 40 mg induced signif-
used for eradication of H. pylori.[31] The eradication rates were icantly more potent acid inhibition than tenatoprazole 20 mg and
80.2%, 97.8% and 100% for EMs, IMs and PMs, respectively esomeprazole 40 mg (24-hour median pH 4.6, 4.0 and 4.2, respec-
(p < 0.05). The efficacy of rabeprazole appeared to be less depen- tively; nocturnal pH 4.7, 4.1 and 3.6, respectively). In addition, the
dent on the CYP2C19 genetic polymorphism. Hokari et al.[32] percentage of time when the pH was >4 was significantly higher
randomly allocated 102 H. pylori-positive patients with gastric during the night for tenatoprazole 40 mg than for esomeprazole
ulcers to three groups: rabeprazole 10 mg, rabeprazole 20 mg or 40 mg (64.3% vs 46.8%) and the NAB duration was significant-
rabeprazole 40 mg plus amoxicillin 750 mg and clarithromycin ly shorter for tenatoprazole 40 mg than for esomeprazole 40 mg. In
200 mg, all given twice daily for 7 days. There was no significant a similar study, Hunt et al.[46] compared tenatoprazole 40 mg with
difference in the eradication rates in EMs compared with PMs esomeprazole 40 mg. At presumed steady state (day 7), the median
(86% vs 77%). In a meta-analysis that examined the evidence 24-hour pH values were 5.02 and 4.79 for tenatoprazole and
relating CYP2C19 polymorphisms to first-line H. pylori eradica- esomeprazole, respectively. There was a significant difference
tion rates, it was found that omeprazole-based dual and triple between tenatoprazole and esomeprazole during the nocturnal
therapies led to significantly higher eradication rates in PMs than period, when the mean pH was 4.64 and 3.61, respectively, and the
in EMs (odds ratio 4.03; 95% CI 1.97, 8.28) and IMs (odds ratio mean percentage of time when the pH was >4 was significantly
2.24; 95% CI 1.09, 4.61).[41] On the other hand, rabeprazole- and higher for tenatoprazole (72.5% vs 62.2%). The effect of
lansoprazole-based dual and triple therapies did not show any tenatoprazole was still present 5 days after treatment withdrawal,
significantly different eradication rates between PMs and EMs. In especially at night-time.
recognition of the potential of pharmacogenomics to guide H. py-
lori eradication therapy, Furuta et al.[42] developed a new assay 3. Conclusion
system for determining CYP2C19 polymorphisms and the H. py-
lori genotype based on gastric biopsy samples. This pharmacoge- Effective management of acid-related disorders depends on the
nomics test was subsequently applied in a clinical trial of H. pylori degree and duration of acid suppression as well as the total
eradication therapy.[43] Based on genetic testing, bacterial suscep- duration of treatment. PPIs are clearly superior to H2RAs in the
tibility to clarithromycin and patient CYP2C19 genotypes were management of acid-related disorders. For any specific PPI,
determined and used to create a tailored therapy. This pharmacokinetics are important with respect to the bioavailability
pharmacogenomics-based therapy was compared with a standard of the PPI. Where the circulating concentrations of PPIs can be
triple therapy. It was found that a pharmacogenomics-based tai- achieved reliably, both the onset of action and the extent of 24-
lored treatment for H. pylori infection led to a significantly higher hour gastric inhibition will depend more on the pharmacodynamic
eradication rate (96% vs 70%) using the initial treatment, without properties of the PPI than on its pharmacokinetics. Theoretically,
increasing the final per-patient cost for successful eradication. all PPIs are similar in terms of their clinical efficacy so long as
Although this finding is promising, more data are needed to correct doses are used relative to their potency. Pharmacokinetic
determine whether such strategies are indeed cost effective. properties such as differences in hepatic metabolism due to
CYP2C19 genetic polymorphisms, as well as a longer elimination
2.3 Elimination Half-Life half-life (as in the case of tenatoprazole), may influence clinical
outcomes. The clinical choice between PPIs may ultimately relate
The currently available PPIs have short elimination half-lives
less to their specific pharmacokinetic properties than to cost,
ranging from 1 to 1.5 hours. A PPI with a longer elimination half-
associated drug and CYP interactions, and specific toxicities.
life may produce more prolonged blockade of proton pumps with
the potential for greater acid suppression and, hence, a greater
clinical effect, particularly for patients with significant postprandi- Acknowledgements
al evening and/or nocturnal symptoms. Tenatoprazole is a new PPI
No sources of funding were used to assist in the preparation of this review.
that has a 5- to 7-fold longer elimination half-life than other
The authors have no conflicts of interest that are directly relevant to the
current PPIs. It could be potentially more useful for the treatment content of this review.
of GORD and NAB.[44]
The effects of tenatoprazole 40 mg versus esomeprazole 40 mg
on intragastric acidity in healthy volunteers were compared in two References
1. Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppres-
studies, and similar results were obtained. Galmiche et al.[45] sion for healing of duodenal ulcers? A model of the relationship between ulcer
compared the effects of 1 week of tenatoprazole 20 mg, healing and acid suppression. Gastroenterology 1990; 99: 345-51
2. Howden CW, Jones DB, Peace KE, et al. The treatment of gastric ulcer with
tenatoprazole 40 mg and esomeprazole 40 mg on intragastric antisecretory drugs: relationship of pharmacological effect to healing rates. Dig
acidity in H. pylori-negative healthy volunteers in a randomised, Dis Sci 1988; 33: 619-24

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (1)
6 Fock et al.

3. Bell NJ, Burget D, Howden CW, et al. Appropriate acid suppression for the 27. Furuta T, Shirai N, Sugimoto M, et al. Effect of concomitant dosing of famotidine
management of gastroesophageal reflux disease. Digestion 1992; 51 Suppl. 1: with lansoprazole on gastric acid secretion in relation to CYP2C19 genotype
59-67 status. Aliment Pharmacol Ther 2005; 22: 67-74
4. Lin H-J, Lo W-C, Lee F-Y, et al. A prospective randomized comparative trial 28. Kawamura M, Ohara S, Koike T, et al. The effects of lansoprazole on erosive
showing that omeprazole prevents rebleeding in patients with bleeding peptic reflux esophagitis are influenced by CYP2C19 polymorphism. Aliment
ulcer after successful endoscopic therapy. Arch Intern Med 1998; 158: 54-8 Pharmacol Ther 2003; 17: 965-73
5. Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in 29. Ariizumi K, Ohara S, Koike T, et al. The therapeutic effects of rabeprazole at a
grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterolo- dose of 10mg on reflux esophagitis may not be influenced by CYP2C19
gy 1997; 112: 1798-810 polymorphism [abstract]. Gastroenterology 2004; 126 Suppl. 2: 340
6. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance 30. Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole
therapies for reflux esophagitis. N Engl J Med 1995; 333: 1106-10 metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.
7. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with Ann Intern Med 1998; 129: 1027-30
ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. N
31. Schwab M, Schaeffeler E, Klotz U, et al. CYP2C19 polymorphism is a major
Engl J Med 1998; 338: 719-26
predictor of treatment failure in White patients by use of lansoprazole-based
8. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for quadruple therapy for eradication of Helicobacter pylori. Clin Pharmacol Ther
acute peptic ulcer bleeding. Cochrane Database Syst Rev 2006 Jan 25; (1): 2004; 76: 201-9
CD002094
32. Hokari K, Sugiyama T, Kato M, et al. Efficacy of triple therapy with rabeprazole
9. AstraZeneca. Nexium® prescribing information [online]. Available from URL: for Helicobacter pylori infection and CYP2C19 genetic polymorphism. Ali-
http://www.nexium.net/hcp/AboutNexium/Nexium-prescribing-informa- ment Pharmacol Ther 2001; 15: 1479-84
tion.aspx?mid=26 [Accessed 2007 Sep 25]
33. Kawai T, Kawakami K, Kataoka M, et al. Comparison of efficacy of dual therapy
10. TAP Pharmaceutical Products Inc. Prevacid® prescribing information [online].
and triple therapy using rabeprazole in second-line eradication of Helicobacter
Available from URL: http://www.prevacid.com/pi.aspx [Accessed 2007
pylori in Japan. Aliment Pharmacol Ther 2006; 24 Suppl. 4: 16-22
Sep 25]
11. AstraZeneca. Prilosec® (omeprazole) delayed release capsules [online]. Available 34. Kurzawski M, Gawrońska-Szklarz B, Wrześniewska J, et al. Effect of
from URL: http://www.astrazeneca-us.com/pi/Prilosec.pdf [Accessed 2007 CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer
Sep 25] patients. Eur J Clin Pharmacol 2006; 62: 877-80
12. Wyeth Pharmaceuticals Inc. Protonix® (pantoprazole sodium) delayed-release 35. Suzuki T, Matsuo K, Sawaki A, et al. Influence of smoking and CYP2C19
tablets [online]. Available from URL: http://www.pantoprazole.com/ [Ac- genotypes on H. pylori eradication success. Epidemiol Infect 2007; 135: 171-6
cessed 2007 Sep 25] 36. Sheu BS, Kao WA, Cheng HC, et al. Esomeprazole 40mg twice daily in triple
13. Eisai Inc. Aciphex® (rabeprazole sodium) delayed-release tablets [online]. Avail- therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19
able from URL: http://www.aciphex.com/pdf/aciphexpi.pdf [Accessed 2007 metabolism. Aliment Pharmacol Ther 2005; 21: 283-8
Sep 25] 37. Gawronska-Szklarz B, Wrzesniewska J, Starzynska T, et al. Effect of CYP2C19
14. Bastaki SM, Chandranath I, Garner A. Comparison of five antisecretory agents and MDR1 polymorphisms on cure rate in patients with acid-related disorders
acting via gastric H+/K+-ATPase. J Physiol Paris 2000; 94: 19-23 with Helicobacter pylori infection. Eur J Clin Pharmacol 2005; 61: 375-9
15. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of 38. Klotz U, Treiber G, Schwab M. Determinants of non-response in Helicobacter
proton pump inhibitors. Aliment Pharmacol Ther 2006; 23 Suppl. 2: 2-8 pylori eradication trials. J Gastroenterol Hepatol 2005; 20: 1471
16. Äbelö A, Andersson T, Antonsson M, et al. Stereoselective metabolism of 39. Manes G. Helicobacter pylori eradication, CYP2C19 and omeprazole doses.
omeprazole by human cytochrome P450 enzymes. Drug Metab Disp 2000; 28: Aliment Pharmacol Ther 2005; 22: 273-4
966-72
40. Chen MC, Hu CT, Wang LY, et al. The efficacy of Helicobacter pylori eradication
17. Andersson T, Hassan-Alin M, Hasselgren G, et al. Pharmacokinetic studies with related to CYP2C19 metabolism. Aliment Pharmacol Ther 2005; 22: 274-5
esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet 2001; 40:
411-26 41. Padol S, Yuan YH, Thabane M, et al. The effect of CYP2C19 polymorphisms on
H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-
18. Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of analysis. Am J Gastroenterol 2006; 101: 1467-75
proton pump inhibitors – emphasis on rabeprazole. Aliment Pharmacol Ther
1999; 13 Suppl. 3: 27-36 42. Furuta T, Sagehashi Y, Shirai N, et al. Influence of CYP2C19 polymorphism and
Helicobacter pylori genotype determined from gastric tissue samples on res-
19. Howden CW. Review article: immediate-release proton-pump inhibitor therapy –
ponse to triple therapy for H. pylori infection. Clin Gastroenterol Hepatol 2005;
potential advantages. Aliment Pharmacol Ther 2005; 22 Suppl. 3: 25-39
3: 564-73
20. Castell D, Bagin R, Goldlust B, et al. Comparison of the effects of immediate-
release omeprazole powder for oral suspension and pantoprazole delayed- 43. Furuta T, Shirai N, Kodaira M, et al. Pharmacogenomics-based tailored versus
release tablets on nocturnal acid breakthrough in patients with symptomatic standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther
gastroesophageal reflux disease. Aliment Pharmacol Ther 2005; 21: 1467-74 2007; 81: 521-8
21. Hellstrom PM. Vitols S. The choice of proton pump inhibitor: does it matter? Basic 44. Scarpignato C, Pelosini I. Review article: the opportunities and benefits of extend-
Clin Pharmacol Toxicol 2004; 94: 106-11 ed acid suppression. Aliment Pharmacol Ther 2006; 23 Suppl. 2: 23-34
22. Pantoflickova D, Dorta G, Ravic M, et al. Acid inhibition on the first day of dosing: 45. Galmiche JP, Des Varannes SB, Ducrotte P, et al. Tenatoprazole, a novel proton
comparison of four proton pump inhibitors. Aliment Pharmacol Ther 2003; 17: pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and
1507-14 comparison with esomeprazole in healthy volunteers. Aliment Pharmacol Ther
23. Lind T, Rydberg L, Kyleback A, et al. Esomeprazole provides improved acid 2004; 19: 655-62
control vs omeprazole in patients with symptoms of gastroesophageal reflux 46. Hunt RH, Armstrong D, James C, et al. Effect on intragastric pH of a PPI with a
disease. Aliment Pharmacol Ther 2000; 14: 861-7 prolonged plasma half-life: comparison between tenatoprazole and es-
24. Miner P, Katz PO, Chen YS, et al. Gastric acid control with esomeprazole, omeprazole on the duration of acid suppression in healthy male volunteers. Am
lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover J Gastroenterol 2005; 100: 1949-56
study. Am J Gastroenterol 2003; 98: 2616-20
25. Fock KM, Teo EK, Ang TL, et al. Rabeprazole vs esomeprazole in non-erosive
gastro-esophageal reflux disease: a randomized, double-blind study in urban Correspondence: Prof. Kwong Ming Fock, Division of Gastroenterology,
Asia. World J Gastroenterol 2005; 11: 3091-8 Department of Medicine, Changi General Hospital, 2 Simei Street 3, Singa-
26. Lim PWY, Goh KL, Wong BCY. Review article: CYP2C19 genotype and the PPIs pore 529889.
– focus on rabeprazole. J Gastroenterol Hepatol 2005; 20: S22-8 E-mail: [email protected]

© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (1)