Yonago Acta medica 2008;51:31–38

Effect of CYP2C19 Polymorphism on Treatment Successin Lansoprazole-Based 7-Day Treatment Regimen
for Cure of H. pylori Infection in Japan
Yosuke Kishimoto*†, Kazuo Yashima‡, Akiko Sano*, Masaharu Koda‡, Tomoyuki
Mukoyama‡, Atsushi Yanagidani‡, Akihide Udagawa‡, Koichiro Kawaguchi‡,Takahiro Nomi‡, Atsushi Kitamura‡, Yasuyoshi Fujii‡, Atsushi Tsutsumi‡, Yuji
Takano‡, Shuji Kitaoka‡, Norimasa Miura*, Masayuki Kitano¶, Naoto Maeda‡,
Akihide Hosoda‡, Goshi Shiota§, Yoshikazu Murawaki‡ and Junichi Hasegawa**Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science,
School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, †Department of Internal Medicine, Hitachi General Hospital, Hitachi 317-0077, ‡Division of Medicine and Clinical
Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, ¶Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kinki University School of Medicine, Osaka-Sayama 589-8511 and§Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative
Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical
Sciences, Tottori University Faculty of Medicine, Yonago 683-8503 Japan

Recently, Helicobacter pylori (H. pylori)-positive peptic ulcer patients were treated by a
1-week triple therapy [lansoprazole (LPZ) 30 mg, amoxicillin 750 mg and clarithromycin
200 or 400 mg, each twice daily] without the checking CYP2C19 genotype in Japan. This
regimen was done to obtain sufficient cure rates for H. pylori infection using a high doseof LPZ (60 mg/day) without the great cost of having to determine the genotype. However, the failure rate for eradicating H. pylori was reported to be 12.5%. The reasons forthis were studied in 33 Japanese patients with H. pylori-positive gastric or duodenal ulcer. Blood samples of the patients were collected to determine the genotype of CYP2C19
and plasma concentrations of LPZ and its metabolites at 3 h postdose on the morning of
the 7th day of treatment. H. pylori infection was cured in 25 of the 33 patients (75.8%).
The cure rate was highest in the group of poor metabolizers (PM), intermediate in
the group of extensive metabolizers of the heterozygous type (htEM) and lowest in thegroup of extensive metabolizers of the homozygous type (hmEM). The relative ratio ofmean plasma concentration for LPZ among the 3 groups was 1.00:1.43:2.93 (hmEM:
htEM:PM groups). Our data suggest that success of the eradication is dependent on the
CYP2C19-related genotypic status or the plasma concentrations of LPZ in a steady state
condition after a multiple dosing regimen; that is to say, checking CYP2C19 is necessary
even on occasions when treatment is done by H. pylori eradication methods as performed
in Japan.
Key words: CYP2C19; Helicobacter pylori; Japan; lansoprazole
Abbreviations: CAM, clarithromycin; Cmax, maximal concentration; EM, extensive metabolizer; hmEM, homozygous
EM; htEM, heterozygous EM; LPZ, lansoprazole; LPZ-SFN, lansoprazole sulfone; OH-LPZ, 5-hydroxylansoprazole;PM, poor metabolizer; PPI, proton pomp inhibitor; RFLP, restriction fragment length polymorphism

31

Y. Kishimoto et al.

soprazole (OH-LPZ) and lansoprazole sulfone(LPZ-SFN) are the 2 major metabolites detectablein plasma (Pearce et al., 1996). An interindividual difference in the activity of CYP2C19 has beenreported in relationship to the metabolic disposition of LPZ: in individuals with a poor metabolizer (PM) phenotype of CYP2C19, the area under
the plasma concentration-time curve of LPZ ismarkedly increased (Sohn et al., 1997; Katsuki etal., 1997; Ieiri et al., 2001). Therefore, acid secretion in PMs of those who are undergoing LPZ
therapy is assumed to be more strongly inhibitedthan in extensive metabolizers (EMs). The activity of CYP2C19 depends on CYP2C19 genotype
status. Recently, Adachi et al. (2000) reported
that the acid-inhibitory effect of LPZ was affected
by CYP2C19 genotype status. Such studies suggest that the usual dose of LPZ for peptic ulcer (30mg a day) may not attain therapeutically sufficientacid suppression in subjects who are homozygous
EMs (hmEMs). In Japan, H. pylori eradication
therapy was approved under the Japanese systemof health insurance in November 2000. Since
then, H. pylori-positive peptic ulcer patients weretreated by a 1-week triple therapy (LPZ 30 mg,
amoxicillin 750 mg and clarithromycin 200 or
400 mg, each twice daily) without checking for
CYP2C19 genotypes in Japan (Satoh, 2002).
The aim of this new regimen was to obtain highplasma concentrations of LPZ and sufficient curerates for H. pylori infection using twice the doseof LPZ (60 mg a day) without the great cost for
determining the genotype. This regimen showedthat the H. pylori eradication rate was 87.5% in2001 (Asaka et al., 2001); that is to say, the failure
rate using this regimen for H. pylori eradication
was 12.5%. The reasons for the failure have notbeen minutely analyzed so far. Accordingly, we
conducted a prospective study in order to examine the reasons for the 1-week LPZ-based triple
therapy regimen (LPZ 30 mg, amoxicillin 750 mg
and clarithromycin 200 or 400 mg, each twice
daily); for instance, we focused on i) the relationship between the CYP2C19 polymorphism andthe plasma concentration of LPZ on the last day (=The prevalence of Helicobacter pylori (H. pylori)
infection has increased with age in the Japanese.
For Japanese born after 1950, the frequency of H.
pylori infection increased at approximately 1%
per year; for those born before 1950 the prevalence was high (70–80%) and relatively constant(Asaka et al., 1992). H. pylori infection was significantly more prevalent in Japanese than in Europeans and Americans (Schlemper et al., 1995).
A high incidence of gastric cancer was reportedly
related to infection with H. pylori (Parsonnet etal., 1991), and the highest incidence rates of gastric cancer in the world are found in Japan (Parkin
et al., 2001). A high prevalence of the infection may portend continued high rates of gastriccancer in the forthcoming years (Uemura et al.,1997). Thus, it is highly important that H. pylori
be eradicated in Japan.
There are many reports available regarding
the predictive factors for successful treatment of
H. pylori, and several host risk factors as well asbacterial factors are known to affect cure rates(Fallone et al., 1999; Kamada et al., 1999; Fujioka, 2000; Hoshiya et al., 2000). One recent
report suggested that a polymorphism in the geneencoding the CYP2C19 enzyme for the proton
pomp inhibitor (PPI) metabolism could affect the
chance for a cure in H. pylori-positive patients
who were treated with a 2-week dual therapy regimen with omeprazole and amoxicillin (Furuta etal., 1998). A recent trend for eradicating H. pylori involves the use of PPI-based triple therapies(Pounder, 1997; Unge, 1997) in order to obtainhigher cure rates of eradication, while the impactof a CYP2C19 genetic polymorphism on the success of eradication in PPI-based triple therapies isstill unclear.
Lansoprazole (LPZ) is a substituted benzimidazole derivative that effectively inhibits gastric acid secretion by irreversibly binding to theproton pump (H+/K+-ATPase) in gastric parietal
cells (Sachs et al., 1995). LPZ is metabolized bya genetically determined S-mephenytoin 4'-hydroxylase [cytochrome P4502C19 (CYP2C19)]
in the liver (Pearce et al., 1996). 5-Hydroxylan32

H. p. eradication by Japanese regimen

polymorphism (PCR-RFLP) analysis as previously described (Ieiri et al., 2001; Kimura et al.,1998).
Patient adherence to therapy and occurrenceof side effects were assessed by interview. Gastroduodenoscopy and determination of H. pylori
infection were done before and 1 month after
treatment. Endoscopists were uninformed ofpatient treatment status and genotypes. Written
informed consent was obtained from each patient
before the study began and our protocol was approved by the ethics review board of Tottori University Faculty of Medicine and Toyooka Hospital.
The susceptibility of each strain of H. pylori
for clarithromycin was assessed in our laboratory
at Tottori University Hospital by determining theminimal inhibitory concentration to the drug using an Etest (Aska Diagnostics, Tokyo, Japan).
Statistical differences in cure rates for H.
pylori infection among the 3 genotype groups
were determined by one-way analysis of varianceand the Fisher exact test. Blood concentrations of
LPZ, OH-LPZ and LPZ-SFN were analyzed forstatistical differences using an unpaired t-test. A
P value of less than 0.05 was considered to be statistically significant.

steady state condition) of a 1-week triple therapy,ii) the relevancy between the CYP2C19 polymorphism and the cure rates of H. pylori infection,iii) existence of anti-biotic resistant H. pylori, iv)
compliance status and v) other factors.

Subjects and Methods
The study samples were collected from 33 Japanese patients with gastric ulcer (n = 18) or duodenal ulcer (n = 15), who attended Tottori University
Hospital or Toyooka Hospital. Twenty-seven patients were male and 6 were female; the mean age(± SD) was 56.8 ± 11.4 years. All patients had
endoscopically proven gastric or duodenal ulcer
and were positive for H. pylori based on plural
evidence from rapid urease testing, culture, 13Curea breath testing and histologic examination.
For eradication of H. pylori, all patients received a 1-week triple therapy comprising LPZ
30 mg, amoxycillin 750 mg and clarithromycin
200 mg, all twice daily with food. Blood samples
were collected to determine the genotype of
CYP2C19 and blood concentrations of LPZ, OHLPZ and LPZ-SFN at 3 h postdose on the morning of the 7th day which was after the beginningof drug administration for H. pylori eradication.
We examined the blood concentrations of LPZ
and its metabolites at 3 h postdose on the morning of the 7th day as parameters to estimate LPZ
pharmacokinetics because the point of blood sampling was in a steady state of LPZ plasma concentration.
The blood samples were centrifuged and theplasma including LPZ and its metabolites wereimmediately collected. The plasma was stored
at –20˚C until analysis. The concentrations of
LPZ and its metabolites were determined by highperformance liquid chromatography (Aoki et al.,1991).
Genomic DNA was prepared from blood
samples using a DNA extractor WB kit (Wako,
Osaka, Japan). The genotype CYP2C19 was
identified using PCR-restriction fragment length

Results
No clinically undesirable signs or symptoms attributable to the therapy were noted during theentire study period. All patients completed thestudy according to protocol. Adherence to theprescribed medication regimen was 100% in all
patients.
Subjects were genotypically classified into
the 3 groups on the basis of PCR-RFLP analysis
for CYP2C19 as shown in Table 1: homozygous
EM group (hmEM), heterozygous EM (htEM)
group and PM group.
H. pylori infection was cured in 25 of the
33 patients (75.8%). The cure rates of H. pylori
infection for the 3 genotype groups are shown in33

Y. Kishimoto et al.

Table 1. Demographic and clinical characteristics of 33 patients with peptic ulcer in the 3 genotype groups
Variable		
		

hmEM
[11]

CYP2C19 status
wt/wt
		

htEM
[16]

PM
[6]

wt/m1† or
wt/m2††

m1/m1‡ or
m1/m2‡‡

plasma concentration was 1.00:0.78:0.47 for OHLPZ and 1.00:5.19:15.71 for LPZ-SFN (hmEM:
htEM:PM groups, respectively); and the mean
concentration of LPZ-SFN in the PM group was
significantly higher than that in the hmEM or
htEM group (P < 0.05).

EM, extensive metabolizer; hmEM, homozygous EM;
htEM, heterozygous EM; PM, poor metabolizer; m1,
CYP2C19 polymorphism in exon 5; m2, CYP2C19 polymorphism in exon 4; wt, wild-type.
[ ], number of patients.
† Heterozygous for CYP2C19m1 without CYP2C19m2.
†† Heterozygous for CYP2C19m2 without CYP2C19m1.
‡ Homozygous for CYP2C19m1 without CYP2C19m2.
‡‡ Heterozygous for both CYP2C19m1 and CYP2C19m2.

Cases in which eradication of H. pylori failed
Four patients (Patients 1 to 4) failed to be curedin the hmEM group (Table 4). Among the 4patients, all strains of H. pylori were antibioticsensitive but the levels of plasma concentrationof LPZ were not enough to eradicate H. pylori.
Because the uptake of clarithromycin (CAM) into
gastric tissue was enhanced in the case of a highpH environment, keeping the intragastric pH atneutral levels by using acid-inhibitory agents suchas LPZ may increase the availability of active antibiotics (Endo et al., 2001a, 2001b). So hmEMs
are impeded in the eradication of H. pylori. Fourpatients (Patients 5 to 8) failed to be cured in the

Table 2. The cure rate was the highest in the PMgroup, intermediate in the htEM group and thelowest in the hmEM group. The cure rate of the
PM group was significantly higher than that of thehmEM group (P < 0.05).
The mean plasma concentrations of LPZ
and its metabolites in relation to the 3 genotype
groups are summarized in Table 3. These plasma
concentrations (Table 3) were measured on themorning of the last day of therapy. An intergenotypic difference was observed for LPZ, OH-LPZ
and LPZ-SFN described as follows: the relative
ratio of mean plasma concentration for LPZ was
1.00:1.43:2.93 (hmEM:htEM:PM groups); themean concentration of LPZ in the PM group was
significantly higher than that in the hmEM or
htEM group (P < 0.05); the relative ratio of mean

Table 2. Cure rates of Helicobacter pylori infection in the 3 genotype groups
Number of patients

Cure rate (%)

11
16
6

7/11 ( 63.6%)
12/16 ( 75.0%)
6/ 6 (100.0%)*

hmEM
htEM
PM

EM, extensive metabolizer; hmEM, homozygous EM;
htEM, heterozygous EM; PM, poor metabolizer.
* P < 0.05 for the PM group compared with the hmEM
group.

Table 3. Mean plasma concentrations of LPZ, OH-LPZ and LPZ-SFN on the morning of the last
day of a 1-week triple therapy
Group

Number of patients

LPZ

OH-LPZ

LPZ-SF

hmEM
htEM
PM

11
16
6

402.4 ± 156.7
573.7 ± 123.1
1181.0 ± 247.8*

31.0 ± 10.5
24.3 ± 6.4
14.5 ± 7.7

6.3 ± 4.5
32.7 ± 11.3
99.0 ± 30.5†

EM, extensive metabolizer; hmEM, homozygous EM; htEM, heterozygous EM; LPZ, lansoprazole; LPZ-SFN, lansoprazole sulfone; OH-LPZ, 5-hydroxylansoprazole; PM, poor metabolizer.
Values are mean ± SEM (ng/mL).
* P < 0.05 for the PM group compared with the hmEM or htEM group.
† P < 0.05 for the PM group compared with the hmEM or htEM group.

34

H. p. eradication by Japanese regimen

Table 4. Antibiotics-sensitive status of H. pylori and plasma concentrations of LPZ, OH-LPZ and LPZSFN on the morning of the last day of a 1-week triple therapy in cases failured for H. pylori eradication
Group

Patient		
numberLPZ

Plasma concentration (ng/mL)		
OH-LPZ
LPZ-SFN

Susceptibility
Sensitive/resistant

hmEM

1
2
3
4

28
149
366
84

< 10
24
23
21

< 10
< 10
< 10
< 10

Sensitive
Sensitive
Sensitive
Sensitive

htEM

5
6
7†
8

807
636
1107
69

53
69
< 10
< 10

< 10
40
150
< 10

Resistant
ResistantSensitive
SensitivePM		All cases of PM were successful for H. pylori eradication.
Mean plasma concentration of LPZ in the PM group was 1181.0 ng/mL as shown in Table 3.

EM, extensive metabolizer; hmEM, homozygous EM; htEM, heterozygous EM; LPZ, lansoprazole; LPZ-SFN, lansoprazole sulfone; OH-LPZ, 5-hydroxylansoprazole; PM, poor metabolizer.
† Patient 7 had an unusual status of treatment for H. pylori eradication as shown in text.

htEM group (Table 4). The strains of H. pylori
were antibiotic (CAM)-resistant in 2 (Patients 5
and 6) of the 4. The strain of H. pylori was antibiotic (CAM)-sensitive, but the level of plasma
concentration of LPZ was not enough to eradicate
H. pylori in 1 (Patient 8) of the 4.
Patient 7 (Table 4) had the following status for treatment of H. pylori eradication: i) 62
year old male, ii) drug compliance was good, iii)
strain of H. pylori was antibiotic-sensitive, iv) noother disease except for peptic ulcer and v) levelof concentration of LPZ was enough to eradicate
H. pylori. This patient had treatment for H. pylori eradication twice. The 1st time was with the
1-week triple therapy (LPZ 30 mg, amoxicillin
750 mg and clarithromycin 200 mg, each twice
daily) and the 2nd time was another 1-week triple
therapy regimen (LPZ 30 mg, amoxicillin 750
mg and clarithromycin 400 mg, each twice daily).
Neither method could produce any successful H.
pylori eradication. On the other hand, all cases in
the PM group were successful for H. pylori eradication (Table 4).

Discussion
Katsuki et al. (1997) have already reported on therelationship between CYP2C19 genotype status
and metabolic disposition of LPZ using the single
oral dose method (single oral administration of
30 mg LPZ) in Japanese subjects, and have shownthat the hydroxylation of LPZ to OH-LPZ was apparently impaired in the PM. However, reports
describing the relationship between CYP2C19
genotype status and metabolic disposition of LPZ
using a multiple-dosing regimen are rare. In
2001, we planned a study using young healthy volunteers who were negative for H. pylori infection
to provide preliminary information that should beconsidered when prescribing LPZ in a multipledose manner with reference to the CYP2C19related genotype status (Ieiri et al., 2001). The
healthy volunteers received 30 mg doses of LPZ
once daily for 8 days and their pharmacokinetic
parameters were measured using blood samples
which were collected on the 8th day. The results
showed that the relative ratio of the maximal
concentration (Cmax) of LPZ was 1.00:1.29:2.00,
that of OH-LPZ 1.00:1.20:0.20 and that of LPZ35

Y. Kishimoto et al.

SFN 1.00:1.00:5.00 (hmEM:htEM:PM groups,
respectively) on the 8th day. These data indicate
the statistical differences of Cmax between any
2 genotypic groups among the 3 groups were notsignificant for LPZ; however, the differences ofCmax between the non-PM (hmEM and htEM)
and PM groups were significant for OH-LPZ and
LPZ-SFN (P < 0.001) (Ieiri et al., 2001).
In the present study, we observed the plasma
concentration on the last day of a 1-week triple
therapy for H. pylori eradication. The mean levels of plasma LPZ and LPZ-SFN in the PM groupwere significantly higher than those in the hmEMor htEM group after the multiple-dosing regimen.
The relative ratio of mean plasma concentration was 1.00:1.43:2.93 for LPZ; 1.00:0.78:0.47
for OH-LPZ and 1.00:5.19:15.71 for LPZ-SFN(hmEM:htEM:PM groups, respectively). These
differences of relative ratio on the 3 genotypic status after a multiple-dose regimen are clearer thanthose of our previous preliminary study using 30
mg doses of LPZ once a day for 8 days (Ieiri etal., 2001).
These differences in the 3 genotypic status
which influence the plasma concentration of LPZ
after a multiple-dose regimen are important,because the cure rates of H. pylori infection are
different according to CYP2C19 genotype status
as shown in Table 2. In Japan, H. pylori-positive
peptic ulcer patients were treated with a 1-week
triple therapy (LPZ 30 mg, amoxicillin 750 mg
and clarithromycin 200 or 400 mg, each twice
daily) without checking for the CYP2C19 genotype. The aim of this method was to obtain highplasma concentrations of LPZ and sufficient curerates for H. pylori infection using two doses of
LPZ (60 mg a day) without the great cost of determining the genotype. In this method, high eradication rates (84–91%) for H. pylori infection were
found in gastroduodenal ulcer patients (Satoh,2002). However, our data suggest that checking
CYP2C19 is necessary even on the occasion oftreatment by H. pylori eradication as it is donein Japan. The cure rate was highest (100.0%) in
the PM group, intermediate (75.0%) in the htEM

group and lowest (63.6%) in the hmEM groupin the present study (Table 2); our data meantthat the success of eradication was dependent on
CYP2C19-related genotypic status or mean plasma concentrations of LPZ in a steady state condition, which is the morning of the last day on the
1-week triple therapy. In Japan, the prevalence ofCAM-resistant H. pylori strains is about 10% to20% (Satoh, 2002). Miki et al. (2003) reported
that the key to successful eradication of H. pylori,using LPZ with CAM and amoxicillin, is CAM
susceptibility, and not a CYP2C19 polymorphism.
However, our results mentioned above indicatethat not only administration of special antibiotics(for example, metronidazole) against CAM-resistant H. pylori strain but also CYP2C19-related
genotypic status should be considered as a countermeasure in the failure of H. pylori eradication.
Under the Japanese regimen for H. pylori eradication, we suggest that CYP2C19 genotyping should
be done when H. pylori eradication fails, and thenan adequate dose of LPZ should be administered
to the patients; in addition to these treatments,
checking the resistance ability of H. pylori against
antibiotics is also important.
By the way, we experienced one case inwhich eradication of H. pylori failed notwithstanding the high level of plasma LPZ concentration, as in the PM group and antibiotic-sensitivity of the H. pylori strain (Patient 7 in Table4). Wermeille et al. (2002) reported that poor
compliance and bacterial resistance could only
explain 40% of the failures in H. pylori eradication. Their report suggests that other factors must
be involved. LPZ is known to be metabolized
via CYP3A4 as well as CYP2C-19 (Pearce et al.,
1996; Ishizaki and Horai, 1999). So CYP3A4
allelic variants may have been involved in the
failure of the eradication in Patient 7 (Table 4).
Several recent studies have reported that CYP3A4
allelic variants exist in Caucasian and AfricanAmerican populations (Paris et al., 1999; Sata etal., 2000; van Schaik et al., 2000; Wandel et al.,2000). However, whether these isoform variants
are associated with the altered metabolism of LPZ
36

H. p. eradication by Japanese regimen

appears to be controversial and conflicting (Sataet al., 2000; Wandel et al., 2000). Because theexistence of CYP3A4-related PMs has not beenreported in any part of the Japanese population sofar, we did not examine CYP3A4-related phenotyping/genotyping factor(s) in the present study.
On the other hand, there is also the possibility that
other factors such as drug absorption or biologicaldrug delivery/distribution may sometimes affecttreatment success. Further examination is neededon these cases.

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Received February 13, 2008; accepted, June 16, 2008
Corresponding author: Junichi Hasegawa, MD, PhD

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