Helicobacter ISSN 1523-5378

Rabeprazole Can Overcome the Impact of CYP2C19

Polymorphism on Quadruple Therapy
Chao-Hung Kuo,*,, Sophie S.W. Wang, Wen-Hung Hsu,* Fu-Chen Kuo, Bi-Chuang Weng, Chia-Jung Li,
Ping-I Hsu, Angela Chen,**, Wen-Chun Hung,**, Yuan-Chieh Yang, Wen-Ming Wang*,
and Deng-Chyang Wu,,
*Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, Division of Gastroenterology, Department of Internal
Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Department of Medicine, Faculty of Medicine, College of Medicine,
Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Gynecology and Obstetrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan,

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University,
Kaohsiung, Taiwan, **Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, National Sun Yat-Sen UniveristyKaoshiung Medical University Joint Center, Kaohsiung, Taiwan, Department of Laboratory Medicine, Kaohsiung Medical University Hospital,
Kaohsiung, Taiwan

Keywords
CYP2C19 genotype, quadruple therapy,
Helicobacter pylori.
Reprint requests to: Deng-Chyang Wu,
Chief of Gastroenterology, Kaohsiung Medical
University Hospital, 100 Tz-You 1st Road,
Kaohsiung City, 807 Taiwan. E-mail: dechwu@
yahoo.com

Abstract
Objectives: The prospective study was designed to clarify the impact of
CYP2C19 on quadruple therapies and survey the efficacies of rabeprazolebased quadruple therapy for Helicobacter pylori infection after failure of
standard triple therapies.
Patients and Methods: From January 2007 to March 2009, 1055 H. pyloriinfected patients received standard triple regimens (proton-pump inhibitor
(PPI), clarithromycin, and amoxicillin). Helicobacter pylori eradication was
achieved in 865 (81.9%) subjects. One hundred ninety eradication-failure
patients were enrolled and randomly assigned to receive a 7-day eradication
therapy. Ninety-six patients were treated with esomeprazole-based quadruple rescue therapies (EB), while 94 patients were treated with rabeprazolebased quadruple rescue therapies (RB). Follow-up endoscopy was done
16 weeks later to assess the treatment response. Patients responses, CYP2C19
genotypes, and antibiotics resistances were also examined.
Results: Intention-to-treat analysis revealed that RB had better eradication
rates than EB (EB: 72.9%; 95% CI: 64.980.9% and RB: 78.7%; 95% CI
72.584.9%) (p value = .543). Per-protocol results were EB = 75.3%; 95%
CI: 70.380.3% and RB = 85.1%; 95% CI: 80.689.6% (p value = .0401).
Both regimens had similar compliance (p value = 0.155) and adverse events
(p value = 0.219). We also surveyed those patients without resistance of any
antibiotics. RB still showed better outcome than EB. Our data showed that
esomeprazole-based regimen and CYP2C19 Hom EM genotype were
important predictors for eradication failure.
Conclusions: In quadruple therapy, rabeprazole-based regimens had better
efficacy than esomeprazole-based regimens. CYP2C19 polymorphism also
played an important role in quadruple therapy. It seems advisable to change
PPI to rabeprazole in second-line quadruple therapy.

According to Maastricht III Consensus Report, indications for anti-Helicobacter pylori therapy include
gastroduodenal ulcer disease, gastric low-grade mucosaassociated lymphoid tissue lymphoma, atrophic gastritis,
and early gastric cancer following endoscopic resection
[1]. Seven-day triple therapy (proton-pump inhibitor
(PPI), amoxicillin, and clarithromycin) has been the

2010 Blackwell Publishing Ltd, Helicobacter 15: 265272

recommended first-line therapy for H. pylori infection in

Taiwan, Europe, and many other countries [2,3].
Currently available first-line anti-H. pylori therapies
may fail in up to 30% of patients [4,5] leading to a
significant increase of antimicrobial resistance, particularly against the key antibiotics clarithromycin and or
metronidazole [6,7]. Therefore, the standard strategy of

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Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

second-line therapy has focused on changing

antibiotics.
However, the effect of PPI influenced by CYP2C19 is
also an important factor of eradication [8]. As is known,
many antibiotics used for eradicating H. pylori are acid
sensitive. PPIs not only increase the activity of some
antibiotics by reducing gastric acid secretion but also
possess direct anti-H. pylori activity [9,10]. They are
metabolized by the hepatic cytochrome P450 system,
especially S-mephenytoin 4-hydroxylase (CYP 2C19)
[11]. A meta-analysis of 17 studies in Asian patients
demonstrated significantly lower H. pylori eradication
rates in homozygous extensive metabolizers (HomEM)
compared to poor metabolizers (PM) exposed to standard triple or dual therapies [12]. Few studies have
focused on the impact of PPI in second-line eradication
therapies. Besides these, current guidelines continue to
recommend antimicrobial susceptibility testing after the
second treatment failure [1]. According to the above
indications, choosing one PPI that is not influenced by
CYP2C19 in second-line therapy may be suitable for
avoiding these confounding factors.
Rabeprazole is considered to be more active against
H. pylori than most PPIs [1315]. One reason is the
higher pKa for the conversion of rabeprazole to the
sulphonamide [16], which means it is converted at a
higher pH than other PPIs, resulting in more rapid
proton-pump inhibition [13]. Furthermore, rabeprazole
and its thio-ether metabolite inhibit the motility and
urease activity of H. pylori [14,15].
The aims of this study were therefore: (1) to compare
the efficacy and safety of 1-week rabeprazole-based and
esomeprazole-based quadruple rescue therapies after
failure of standard esomeprazole-based first-line therapy
and (2) to explore the effect of PPI influenced by
CYP2C19 polymorphisms on treatment outcome of
second-line eradication.

Materials and Methods

Participants
The treatment group was any patient visiting the
gastroenterological clinics of Kaohsiung Medical University Hospital (KMUH) and Kaohsiung Veteran General
Hospital (KVGH) between June 2005 and July 2008
with the complaint of dyspepsia. These H. pyloriinfected patients received first-line eradication therapies
with standard triple regimen (esomeprazole (40 mg)
twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily). All of the patients underwent
endoscopic examination with biopsy of the gastric
mucosa or a 13C-urea breath test (UBT) to establish

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Kuo et al.

H. pylori infection status after previous eradication therapy. The presence of H. pylori was defined as (1) at least
two positive results of rapid urease test, histology, and
13
C urea breath test; or (2) a positive result of culture.
Then, the eradication-failure patients were enrolled for
this study after signing informed consent. Exclusion
criteria included (a) ingestion of antibiotics, bismuth, or
PPI within the prior 4 weeks; (b) patients with allergic
history to the medications used; (c) patients with previous gastric surgery; (d) the coexistence of serious
concomitant illness (e.g., decompensated liver cirrhosis,
uremia); and (e) pregnant women.

Questionnaire
The questionnaire contained questions regarding
personal history of smoking and alcohol drinking. Smokers were those who consumed more than one pack of
cigarettes a week and drinkers were those who drank
more than one cup of alcoholic beverage a day. Compliance was defined as good (taken more than 80% of the
total medication) or poor, by counting unused medication after the treatment was completed. The adverse
events included abdominal pain, diarrhea, constipation,
dizziness, taste perversion, headache, anorexia, nausea,
vomiting, and skin rash. Those who considered those
symptoms disturbed their daily life were defined to have
positive adverse effects. Those who did not experience
these symptoms were defined as negative adverse effects.

Diagnosis of H. pylori Infection

Culture and pathological examination.
Biopsy specimens were rubbed on the surface of a
Columbia blood agar plate and then incubated at 35 C
under microaerobic conditions for 45 days. The result
for the Grams stain was considered positive when a
curvy, Gram-negative bacterium on the smear was
found. Culture of H. pylori was considered positive if
one or more colonies showed Gram negativity, oxidase
(+), catalase (+), urease (+), and spiral or curved rods
in morphology. The biopsy specimens were fixed with
formalin, embedded in paraffin, and stained with
hematoxylin and eosin. They were interpreted and
reported on by the same pathologist. This method
provided additional information about gastric mucosal
changes, including atrophy, dysplasia, metaplasia, and
the pattern and degree of inflammation.

Rapid Urease Test

The results of CLO test (Delta West Bentley, WA
Australia) were interpreted as positive if the color of

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Kuo et al.

the gel turned pink or red 6 hours after examination at

room temperature.
13

C-UBT

The 13C-urea was manufactured by the Institute of

Nuclear Energy Research, Taiwan. One hundred milliliters of fresh whole milk was used as the test meal. This
detailed procedure was reported in our previous study
[17]. For patients who received follow-up endoscopy,
H. pylori infection was established if the culture was
positive, or both CLO test and histology were positive.

Culture and Antimicrobial Resistance

One antral gastric biopsy specimen was obtained for
isolation of H. pylori, using previously described culture
methods [18]. Helicobacter pylori culturing was done by
rubbing the specimens on the surface of a Campy-BAP
agar plate (Brucella agar (Difco, Sparks, MD, USA) +
IsoVitalex (Gibco, Grand Island, NY, USA) + 10%
whole sheep blood). Then, they were incubated at
37 C under microaerobic conditions (5% O2, 10%
CO2, and 85% N2) for 45 days. The results were
considered positive if one or more colonies of Gramnegative bacilli with positive oxidase, catalase, and
urease tests were found. The H. pylori strains were
tested for tetracycline, metronidazole, amoxicillin, and
clarithromycin susceptibility using the E-test (AB Biodisck, Solna, Sweden). Helicobacter pylori strains with a
minimal inhibitory concentration value >4, >8, >0.5,
and >1 mg L were considered to be resistant to tetracycline, metronidazole, amoxicillin, and clarithromycin.

Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

questionnaire to obtain demographic data and medical

history. The participants were randomly assigned to two
groups treated with quadruple therapies: the esomeprazole-based quadruple therapy group (esomeprazole
40 mg twice daily, bismuth subcitrate 120 mg four times
daily, tetracycline 500 mg four times daily, and metronidazole 250 mg four times daily for 7 days) or the rabeprazole-based quadruple therapy group (rabeprazole
20 mg twice daily, bismuth subcitrate 120 mg four times
daily, tetracycline 500 mg four times daily, and metronidazole 250 mg four times daily for 7 days). Patients were
asked to return during the second week to assess drug
compliance and adverse effects. Endoscopy with biopsy
for rapid urease test, histology and culture was repeated
16 weeks later to confirm H. pylori infection status. For
patients who refused follow-up endoscopy, UBT was
used to confirm H. pylori status. The technicians, who
performed the H. pylori tests (culture, rapid urease test,
and UBT) or filled in the questionnaires as well as the
pathologists, were blinded to the eradication regimens
the patients received. All participants gave written
informed consent. This study was approved by the
Institutional Review Board and ethics committee of
Kaohsiung Medical University Hospital.

Objectives
In this study, we tested the hypothesis that the rabeprazole-based quadruple therapy would be more effective than esomeprazole-based quadruple therapy.
Another hypothesis would be testing that antibiotics
resistances and CYP2C19 genotypes would influence
the outcome of rescue therapy.

Analysis of CYP2C19 Genotypes

Outcomes

For analysis of CYP2C19 genotypes, all enrolled patients

peripheral blood leukocytes were obtained before the
eradication therapy was begun. DNA was extracted
from the leukocytes with a commercially available kit
(QIAGEN K.K., Tokyo, Japan) and stored until use.
Genotyping procedures for identifying the CYP2C19 wild
type (wt) gene and two mutated alleles, CYP2C19 m1 and
CYP2C19 m2, were performed by a polymerase chain
reactionrestriction fragment length polymorphism
method with allele-specific primers [19,20].

The primary endpoint of our study was successful eradication of H. pylori. There were additional analyses about
adverse events during therapies.

Interventions
We included 192 cases (81 men, 111 women; mean
age = 50.7 11.5 years, range: 2072 years) who met
eradication failure of H. pylori infection. They were interviewed by a trained interviewer who used a standardized

2010 Blackwell Publishing Ltd, Helicobacter 15: 265272

Randomization
A computer-generated randomization list was used to
generate random sequence. In addition, we used a
method of combined blocking and stratified randomization to make sure of a close balance of the numbers
and patients characteristics in each group. We set separate randomization within each of two subsets of participants (age and sex). We also set a block of every 10
participants. A computer-generated randomization list
was drawn up by the statistician and given to our
assistant member responsible for randomization. The
collaborating doctors found the patients suitable for

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Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

being enrolled into this study and allocated the next

available number on entry into the trial, then each
patient collected his tablets directly from the hospital
pharmacy. The code was revealed to the researchers
once recruitment, data collection, and laboratory analyses were complete. All study participants and doctors
except the data monitoring committee were blinded to
treatment assignment for the duration of this study.
The data monitoring committee did not contact participants. During this period, we performed two rounds of
the questionnaire to confirm the success of blinding.

Statistical Analysis
The distribution of gender and the initial endoscopic
diagnosis between subjects in EBTM (esomeprazole,
bismuth subcitrate, tetracycline, and metronidazole)
and RBTM (rabeprazole, bismuth subcitrate, tetracycline, and metronidazole) groups were compared by
chi-squared statistics. The same method was applied to
compare the efficacy and the frequency of side effects of
the two regimens. The analyzed efficacy outcome was
cure of H. pylori infection. The difference of patients
ages in the two groups was examined using Students
t-test. A two-sided p value of <.05 was considered statistically significant. The data were analyzed using the
SAS statistical package; all p values were two-sided.
Eradication rates were evaluated by intention-to-treat
(ITT) and per protocol (PP) analyses. ITT analysis
included all randomly assigned patients who had taken
at least one dose of study medication. Patients whose
infection status was unknown following treatment were
considered treatment failures for the purposes of ITT
analysis. The PP analysis excluded patients with
unknown H. pylori status following therapy and those
with major protocol violations. A p value <.05 was
considered statistically significant. To determine the
predictors affecting the treatment response, clinical, and
bacterial parameters were analyzed by univariate analysis. Significant levels were determined with the use of
two-tailed tests.

Results
Characteristics of the Study Groups
A total of 1085 H. pylori-infected patients received firstline eradication therapies with standard triple regimens.
Helicobacter pylori eradication was achieved in 872
(80.6%) subjects. Twenty-one patients refused to be
enrolled into this study. A total of 192 H. pylori-infected
patients were enrolled in our study and randomly
assigned to esomeprazole-based quadruple therapy

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Kuo et al.

Table 1 Demographic distribution of the subjects receiving different

eradication regimens

No. of patients
MF
Age (year) mean SD
Diagnosis
Gastritis
DU
GU
DU + GU
Polyp
CA
Smoker

EBTM

RBTM

p value

96
41 55
50.57 12.23

94
38 56
50.78 10.78

.7496
.9904

33
6
49
1
3
0
72 94

27
4
39
4
11
1
81 88

.0971

.0044

EBTM, esomeprazole, bismuth subcitrate, tetracycline, and metronidazole; RBTM, rabeprazole, bismuth subcitrate, tetracycline, and metronidazole; M F, male female; DU, duodenal ulcer; GU, gastric ulcer.

(n = 96) or rabeprazole-based quadruple therapy

(n = 96). The clinical characteristics of patients at entry
are summarized in Table 1. Two groups had comparable
age, gender, history of smoking, and endoscopic findings. Among the subjects, two patients retracted their
permission after randomization to the rabeprazole-based
group. They did not receive our studys regimens. The
other subjects were all included in the ITT analysis for
H. pylori eradication. Besides this, four with poor compliance and six lost to follow-up were excluded from PP
analysis for H. pylori eradication. Figure 1 summarizes
patient distribution.

Eradication of H. pylori
Table 2 lists the eradication rates of the EBTM and
RBTM groups. Intention-to-treat analysis revealed that
both groups showed similar eradication rates (EB:
72.9%; 95% CI: 64.980.9% and RB: 78.7%; 95% CI:
72.584.9%) (p value = .543). Per-protocol results were
EB = 75.3%; 95% CI: 70.380.3% and RB = 85.1%;
95% CI: 80.689.6% (p value = .0401). Both regimens
had similar compliance (p value = .155) and adverse
events (p value = .219). Logistic regression analysis
showed that esomeprazole-based regimen and CYP2C19
HomEM genotype were important predictors for
eradication failure.

Factors Influencing Efficacy of anti-H. pylori

Therapy
Table 3 lists the clinical and bacterial factors that might
predict the efficacy of eradication therapy. In univariate
analyses, the eradication rates were significantly related

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Kuo et al.

Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

Figure 1 Deposition of patients. ITT, intention-to-treat; PP, per protocol; EBTM, esomeprazole, bismuth subcitrate, tetracycline, and metronidazole
group; RBTM, rabeprazole, bismuth subcitrate, tetracycline, and metronidazole group; H. pylori, Helicobacter pylori.

to drug compliance (p = .027). Besides this, the genotype of CYP2C19 was a significantly influential factor
(p = .030). But resistances of antibiotics did not influence the outcome of quadruple therapies in our study
(p = .605). No other factors were found to influence the
eradication efficacy significantly in univariate analysis.

tetracycline. Metronidazole-, amoxicillin-, clarithromycin-, and levofloxacin-resistant strains were found in

57.0% (53 93), 4.3% (4 93), 66.7% (62 93), and
22.6% (21 93) of the patients, respectively. Twentytwo patients (15 patients in the EBTM group and seven
in the RBTM group) did not have any resistance among
these 93 patients.

Antibiotic Resistance
Helicobacter pylori strains were isolated from 93 of all
enrolled patients who underwent bacterial culture in
initial endoscopy. One strain developed resistance to

2010 Blackwell Publishing Ltd, Helicobacter 15: 265272

The Genotypes of CYP 2C19

For CYP2C19 genetic polymorphism, six different allelic
patterns were noted: wt wt, wt m1, wt m2, m1 m1,

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Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

Table 2 The outcomes of EBTM and EAL rescue therapies

EBTM
Eradication rate
Intention-to-treat
Per-protocol
Compliance
Adverse events

70 96
70 93
92 93
56 93

RBTM

(72.9)
(75.3)
(98.9)
(60.2)

74 94
74 87
84 87
45 87

Table 4 Adverse events of EBTM and RBTM quadruple therapies

p value

(78.7)
(85.1)
(96.6)
(51.7)

.5430
.0401
.1545
.2190

Values in parentheses are percentages.

In this analysis, patients with unknown outcome are counted as
treatment failures.
EBTM, esomeprazole, bismuth subcitrate, tetracycline, and metronidazole; RBTM, rabeprazole, bismuth subcitrate, tetracycline, and
metronidazole.

Table 3 Logistic regression model analysis of the clinical factors

influencing the efficacy of quadruple therapy
Parameters

Number of patients

Age
<60
156
360
34
Sex
Male
79
Female
111
Smoker
())
159
(+)
31
Compliances
Good
175
Poor
5
Metronidazole resistance
(+)
53
())
40
Tetracycline resistance
(+)
1
())
92
CYP2C19
HomEM
60
HetEM + PM
95

Eradication rate

p value

115 156 (73.7)

29 34 (85.3)

.068

60 79 (75.9)
84 111 (75.7)

.8038

122 153 (79.7)

22 29 (75.8)

.7079

141 175 (80.5)

3 5 (60)

.02700

40 53 (75.5)
32 40 (80)

.6051

1 1 (100)
71 92 (77.2)

.5871

41 60 (68.3)
83 95 (87.4)

.0303

Adverse events (N)

EBTM

Abdominal pain
Diarrhea
Constipation
Headache
Anorexia
Nausea
Vomiting
Skin rash
Dizziness
Bad taste
Fatigue

12 93
5 93
4 93
11 93
16 93
28 93
11 93
8 93
28 93
34 93
41 93

RBTM
(12.9)
(5.3)
(4.3)
(11.8)
(17.2)
(30.1)
(11.8)
(8.6)
(30.1)
(36.6)
(44.1)

5 87
5 87
2 87
6 87
9 87
13 87
17 87
4 87
18 87
15 87
13 87

p value
(5.7)
(5.7)
(2.3)
(6.9)
(10.3)
(14.9)
(19.5)
(4.6)
(20.7)
(17.2)
(14.9)

.096
.9284
.4461
.2482
.1739
.0138
.1637
.2729
.1360
.0031
<.0001

Values in parentheses are percentages.

The numbers of patients who suffered from mild, moderate, and
severe adverse events are presented.
EBTM, esomeprazole, bismuth subcitrate, tetracycline, and metronidazole; RBTM, rabeprazole, bismuth subcitrate, tetracycline, and
metronidazole.

according to CYP2C19 genotype in Table 3. The eradication rates of HomEM, HetEM, and PM were 68.3%
(41 60), 87.7% (64 73), and 86.4% (19 22). A significantly poor cure rate was observed in the CYP2C19 EM
group (CYP2C19 EM vs CYP2C19 HetEM + PM, p = .03).

Adverse Events and Complications

Values in parentheses are percentages.

EBTM, esomeprazole, bismuth subcitrate, tetracycline, and metronidazole; RBTM, rabeprazole, bismuth subcitrate, tetracycline, and metronidazole; CYP, cytochrome P450; EM, extensive metabolizers; PM, poor
metabolizers.

m1 m2, and m2 m2. Patients were classified into three

groups according to genotype: (1) those without mutation (wt wt; n = 60, 38.7%), designated as the HomEM;
(2) those with one mutation (wt m1 or wt m2; n = 73,
47.1%), designated as the heterozygous extensive
metabolizer group (HetEM); and (3) those with two
mutations (m1 m1 or m1 m2 or m2 m2; n = 22, 14.2%),
designated as the PM group. We show the cure rate

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Kuo et al.

The incidence of adverse events during eradication in

two groups was similar (p = .219) and did not result in
significantly different compliance between two groups.
Both groups displayed similar compliance rates (EBTM
98.9% and RBTM 96.7%, p = .154). However, the rates
of nausea, bad taste, and fatigue were significantly
higher in EBTM group. Fatigue was the most common
adverse event. Four patients discontinued treatment
due to adverse events. Interviews regarding adverse
events were carried out in all patients (Table 4).

Discussions
The efficacies of two quadruple therapies used in our
study were similar as in previous reports [2123]. There
were no obvious differences of compliance and side
effects between the two groups. However, better eradication outcome was revealed in rabeprazole-based therapy (PP:R-B 85.17% vs E-B 75.3%, p = .0401). Our
result showed that it is advisable to change PPI to
rabeprazole in second-line therapy. The major disadvantages of quadruple therapy include a complex dosing
regimen and a relatively high number of adverse events
resulting in impaired patient compliance. In our study,

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Kuo et al.

the side effects were acceptable, and patient compliance

was good in both groups. The common side effects of
quadruple therapies include abdominal symptoms (e.g.,
abdominal pain, diarrhea, constipation, and nausea),
skin rash, headache, and dizziness. In our study, fatigue
was the most common adverse effect complained about.
Most adverse events were self-limited.
Resistance to antibiotics (especially clarithromycin)
has been shown to increase considerably in patients
who failed standard therapies. According to Maastricht
III suggestions, standard second-line therapy contains
metronidazole and the resistance rate to this is also high
[6,7], therefore, the reasons why patients encountered
failure of eradication should mainly relate to antibiotic
resistance. In addition, the best method to avoiding
resistance is performing a susceptibility test. But
whether or not susceptibility testing prior to second-line
treatment is useful, still remains controversial [24,25].
On the other hand, the influence of CYP 2C19 genotypes exists and should be considered. Therefore, we
analyzed the outcome of patients without any resistance
to antibiotics used in quadruple therapies. It revealed
that the rabeprazole-based group still had higher eradication rate than the esomeprazole group (100% (7 7) vs
80% (12 15)). Three patients in the esomeprazole-based
group met eradication failure; two were HomEM genotype and one was HetEM genotype. Our data supported
the notion that CYP2C19 genotypes played an important
role in quadruple therapy, consequently, we believe
that the strategy of overcoming eradicating failure lies
not only in changing antibiotics. This finding has not
been strongly focused on in previous studies.
It is now known that the efficacy of omeprazolebased H. pylori therapy is dependent on the CYP2C19
genotype. Omeprazole-based therapies with duration
>7 days give significantly higher eradication rates in
CYP2C19 PMs than in HomEM [12]. In our study, we
used an esomeprazole-based regimen. Esomeprazole
has minimal first pass metabolism, undergoes less
hydroxylation via CYP2C19 and has been shown to
have greater gastric acid suppression effect than omeprazole [26,27]. In additionally, previous studies showed
high-dose esomeprazole-based therapy provide high
and consistent eradication rates (8696%) [2830]. The
dose of esomeprazole that patients received in esomeprazole-based first-line therapy was 20 mg. So we used
the high dose of esomeprazole to overcome the influence of CYP2C19 polymorphism. However, we have
still shown that rabeprazole-based quadruple therapy
also had higher eradication rate than esomeprazolebased quadruple therapy.
Few previous studies have discussed the impact of
CYP2C19 polymorphisms on rescue therapies, and

2010 Blackwell Publishing Ltd, Helicobacter 15: 265272

Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

most of these have focused particularly on non-Asian

patient populations [8]. Previous reports showed
higher percentages of PMs in Asians [31,32]. Our data
showed CYP2C19 polymorphism still had marked
influence on quadruple therapies and this might be
the reason of better eradication outcome in the RBTM
group.
Although rabeprazole has been suggested to be the
PPI least affected by CYP2C19 genotype [33], the eradication rate of a rabeprazole regimen has been shown to
correlate with the CYP2C19 genotype [3436]. Furthermore, the concentration of rabeprazole thioether, the
major metabolite of rabeprazole with anti-H. pylori
activity, is higher in CYP2C19 PM [33,37].
It is important to treat patients according to Maastricht III guidelines. In facing the increasing resistance
of antibiotics, it is advisable to choose a PPI which is
not strongly influenced by CYP2C19 genotypes. In our
study, we wanted to clarify the predictors of quadruple
therapy and the impact of CYP2C19 genotypes on eradication outcome. Our result disclosed another important
strategy for second-line therapy where the PPI might be
changed to rabeprazole to avoid the negative impact of
CYP2C19 genotypes.

Acknowledgements and Disclosures

This work was supported by grants from Kaohsiung Medical
University (Q97031), Kaohsiung Medical University Hospital
(KMUH97-7R31), and National Science Council (NSC 982314-B-037 -045 -MY2) and Excellence for cancer research
center grant, NO.DOH99-TD-C-111-002, Department of
Health, Executive Yuan, Taiwan, ROC.

References
1 Malfertheiner P, Megraud F, OMorain C, Bazzoli F, El-Omar
E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current
concepts in the management of Helicobacter pylori infection:
the Maastricht III Consensus Report. Gut 2007;56:77281.
2 Malfertheiner P, Megraud F, OMorain C, Hungin AP, Jones R,
Axon A, Graham DY, Tytgat G, European Helicobacter Pylori
Study Group (EHPSG). Current concepts in the management of
Helicobacter pylori infectionthe Maastricht 2-2000 Consensus
Report. Aliment Pharmacol Ther 2002;16:16780.
3 Bytzer P, OMorain C. Treatment of Helicobacter pylori. Helicobacter 2005;10(Suppl 1):406.
4 Fennerty MB, Lieberman DA, Vakil N, Magaret N, Faigel DO,
Helfand M. Effectiveness of Helicobacter pylori therapies in a
clinical practice setting. Arch Intern Med 1999;159:15626.
5 Della Monica P, Lavagna A, Masoero G, Lombardo L, Crocella
L, Pera A. Effectiveness of Helicobacter pylori eradication
treatments in a primary care setting in Italy. Aliment Pharmacol
Ther 2002;16:126975.
6 Heep M, Kist M, Strobel S, Beck D, Lehn N. Secondary resistance among 554 isolates of Helicobacter pylori after failure of
therapy. Eur J Clin Microbiol Infect Dis 2000;19:53841.

271

Rabeprazole and CYP2C19 Polymorphism on Quadruple Therapy

7 Wang WH, Wong BC, Mukhopadhyay AK, et al. High prevalence of Helicobacter pylori infection with dual resistance to
metronidazole and clarithromycin in Hong Kong. Aliment Pharmacol Ther 2000;14:90110.
8 Kirsch C, Morgner A, Miehlke S. Relevance of cytochrome
P450 polymorphisms in the treatment of Helicobacter pylori
infection and gastroesophageal reflux disease. Curr Pharmacogenomics 2006;4:4756.
9 Spengler G, Molnar A, Klausz G, Mandi Y, Kawase M,
Motohashi N, Molnar J. Inhibitory action of a new proton
pump inhibitor, trifluoromethyl ketone derivative, against the
motility of clarithromycin-susceptible and-resistant Helicobacter
pylori. Int J Antimicrob Agents 2004;23:6313.
10 Figura N, Crabtree JE, Dattilo M. In-vitro activity of lansoprazole against Helicobacter pylori. J Antimicrob Chemother
1997;39:58590.
11 Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A,
Ishizaki T. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab
Pharmacokinet 2005;20:15367.
12 Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH. The effect
of CYP2C19 polymorphisms on H. pylori eradication rate in
dual and triple first-line PPI therapies: a meta-analysis. Am J
Gastroenterol 2006;101:146775.
13 Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of
the gastric H,K-ATPase with extracytoplasmic thiol reagents.
J Biol Chem 1997;272:2243846.
14 Tsutsui N, Taneike I, Ohara T, Goshi S, Kojio S, Iwakura N,
Matsumaru H, Wakisaka-Saito N, Zhang HM, Yamamoto T. A
novel action of the proton pump inhibitor rabeprazole and its
thioether derivative against the motility of Helicobacter pylori.
Antimicrob Agents Chemother 2000;44:306973.
15 Tsuchiya M, Imamura L, Park JB, Kobashi K. Helicobacter
pylori urease inhibition by rabeprazole, a proton pump inhibitor. Biol Pharm Bull 1995;18:10536.
16 Sachs G, Shin JM, Vagin O, Lambrecht N, Yakubov I, Munson
K. The gastric H,K ATPase as a drug target: past, present, and
future. J Clin Gastroenterol 2007;41(Suppl 2):S22642.
17 Wu IC, Ke HL, Lo YC, Yang YC, Chuang CH, Yu FJ, Lee YC,
Jan CM, Wang WM, Wu DC. Evaluation of a newly developed
office-based stool test for detecting Helicobacter pylori: an
extensive pilot study. Hepatogastroenterology 2003;50:17615.
18 Hsu PI, Hwang IR, Cittelly D, Lai KH, El-Zimaity HM, Gutierrez
O, Kim JG, Osato MS, Graham DY, Yamaoka Y. Clinical presentation in relation to diversity within the Helicobacter pylori
cag pathogenicity island. Am J Gastroenterol 2002;97:22318.
19 De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect
responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994;46:5948.
20 de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer
UA, Goldstein JA. The major genetic defect responsible for the
polymorphism of S-mephenytoin metabolism in humans. J Biol
Chem 1994;269:1541922.
21 Lamouliatte H, Megraud F, Delchier JC, et al. Second-line
treatment for failure to eradicate Helicobacter pylori: a
randomized trial comparing four treatment strategies. Aliment
Pharmacol Ther 2003;18:7917.
22 Cheng HC, Chang WL, Chen WY, Yang HB, Wu JJ, Sheu BS.
Levofloxacin-containing triple therapy to eradicate the

272

Kuo et al.

23

24

25

26

27

28

29

30

31

32

33
34

35

36

37

persistent H. pylori after a failed conventional triple therapy.

Helicobacter 2007;12:35963.
Morgner A, Labenz J, Miehlke S. Effective regimens for the
treatment of Helicobacter pylori infection. Expert Opin Investig
Drugs 2006;15:9951016.
Miwa H, Nagahara A, Kurosawa A, Ohkusa T, Ohkura R, Hojo
M, Enomoto N, Sato N. Is antimicrobial susceptibility testing
necessary before second-line treatment for Helicobacter pylori
infection? Aliment Pharmacol Ther 2003;17:154551.
Wong WM, Gu Q, Chu KM, Yee YK, Fung FM, Tong TS, Chan
AO, Lai KC, Chan CK, Wong BC. Lansoprazole, levofloxacin
and amoxicillin triple therapy vs. quadruple therapy as secondline treatment of resistant Helicobacter pylori infection. Aliment
Pharmacol Ther 2006;23:4217.
Hassan-Alin M, Andersson T, Bredberg E, Rohss K. Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects. Eur J Clin
Pharmacol 2000;56:66570.
Dent J. Review article: pharmacology of esomeprazole and
comparisons with omeprazole. Aliment Pharmacol Ther
2003;17(Suppl 1):59.
Hsu PI, Lai KH, Lin CK, et al. A prospective randomized trial of
esomeprazole- versus pantoprazole-based triple therapy for
Helicobacter pylori eradication. Am J Gastroenterol
2005;100:238792.
Anagnostopoulos GK, Tsiakos S, Margantinis G, Kostopoulos P,
Arvanitidis D. Esomeprazole versus omeprazole for the eradication of Helicobacter pylori infection: results of a randomized
controlled study. J Clin Gastroenterol 2004;38:5036.
Sheu BS, Kao AW, Cheng HC, Hunag SF, Chen TW, Lu CC,
Wu JJ. Esomeprazole 40 mg twice daily in triple therapy and
the efficacy of Helicobacter pylori eradication related to
CYP2C19 metabolism. Aliment Pharmacol Ther 2005;21:2838.
Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and
proton pump inhibitors. Basic Clin Pharmacol Toxicol 2004;95:2
8.
Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn
PM, Evans DA. Frequencies of the defective CYP2C19 alleles
responsible for the mephenytoin poor metabolizer phenotype
in various Oriental, Caucasian, Saudi Arabian and American
black populations. Pharmacogenetics 1997;7:5964.
Williams MP, Pounder RE. Review article: the pharmacology of
rabeprazole. Aliment Pharmacol Ther 1999;13(Suppl 3):310.
Inaba T, Mizuno M, Kawai K, Yokota K, Oguma K, Miyoshi M,
Take S, Okada H, Tsuji T. Randomized open trial for comparison of proton pump inhibitors in triple therapy for Helicobacter
pylori infection in relation to CYP2C19 genotype. J Gastroenterol
Hepatol 2002;17:74853.
Horai Y, Kimura M, Furuie H, et al. Pharmacodynamic effects
and kinetic disposition of rabeprazole in relation to CYP2C19
genotypes. Aliment Pharmacol Ther 2001;15:793803.
Lin CJ, Yang JC, Uang YS, Chern HD, Wang TH. Time-dependent amplified pharmacokinetic and pharmacodynamic
responses of rabeprazole in cytochrome P450 2C19 poor metabolizers. Pharmacotherapy 2003;23:7119.
Yasuda S, Horai Y, Tomono Y, Nakai H, Yamato C, Manabe K,
Kobayashi K, Chiba K, Ishizaki T. 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 1995;58:14354.

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