Review Article

Indian J Med Res 127, June 2008, pp 521-530

Genetic polymorphism of CYP2C19 & therapeutic response to

proton pump inhibitors
A.S. Chaudhry, R. Kochhar* & K.K. Kohli

Departments of Biochemistry & *Gastroenterology, Postgraduate Institute of Medical Education &

Research, Chandigarh, India

Received January 15, 2007

Proton pump inhibitors (PPIs) are extensively metabolized in the liver by CYP2C19, that
demonstrates genetic polymorphism with 21 mutant alleles. The subjects can be divided into 2
groups with respect to CYP2C19 phenotypes viz., extensive metabolizers (EMs) and poor metabolizers
(PMs) of PPIs. This division results in marked interindividual variations in the pharmacokinetics
and pharmacodynamics of PPIs in the population. Intragastric pH values and the plasma
concentration of PPIs after oral ingestion were significantly lower in EMs namely normal
homozygotes (CYP2C19*1/*1) and heterozygotes (CYP2C19*1/*X) compared to PMs namely mutant
homozygotes (CYP2C19*X/*X) where X represents the mutant allele. Hence, association has been
found between the genetic polymorphism of CYP2C19 and therapeutic response to PPIs. CYP2C19
polymorphism affected eradication of Helicobacter pylori using diferent PPI based eradication
therapies as PM patients demonstrated significantly higher eradication rates compared to EMs.
CYP2C19 genetic polymorphism also affects the therapeutic outcome of gastroesophageal reflux
disease (GERD), reflux oesophagitis and duodenal ulcers. For optimal therapeutic response with
PPIs, CYP2C19 pharmacogenetics should be taken into consideration. This shall help in the
prescription of optimal doses of PPIs, thus paving the way for personalized medication.

Key words CYP2C19 - Helicobacter pylori - pharmacogenetics - proton pump inhibitors

Cytochromes P450 (CYPs) are the drug metabolizing

enzymes found primarily in the liver. Inter-individual
variations in the metabolism of drugs have been observed
in different ethnic groups due to the occurrence of genetic
polymorphism of the drug metabolizing enzymes. Genetic
polymorphism is the occurrence of a variant allele with a
frequency of 1 per cent or greater in a population. Although
various allelic forms of different CYPs have been reported,
functional polymorphism has only been established for
CYP2A6, CYP2C9, CYP2C19 and CYP2D61. On the basis

of genetic polymorphism a population may be divided into

two groups namely extensive metabolizers (EMs)
demonstrating normal metabolism of the drugs and poor
metabolizers (PMs) demonstrating impaired metabolism
of drugs due to the deficiency of CYPs. The first PM of
mephenytoin, a probe drug for CYP2C19, was reported
by Kupfer et al in 19792. Subsequently the genetic basis
of CYP2C19 PM trait was demonstrated3,4. Omeprazole
(OPZ)5 and proguanil6 are the other probe drugs used to
assess the activity of CYP2C19. Subjects having a log
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INDIAN J MED RES, JUNE 2008

hydroxylation index value more than 1.7 for OPZ5 and a

urinary proguanil to cycloguanil ratio6 greater than 10 are
classified as PMs. CYP2C19 gene is located on long arm
of chromosome 10 (10q24.1-10q24.3). It has 9 exons and
8 introns. The cDNA is 1473 bp in length. Twenty one
mutant alleles of CYP2C19 have been reported3,4,7-11
(Fig.). CYP2C19*2 to CYP2C19*8 were discovered in the
subjects who demonstrated decreased ability to metabolize
the probe drugs, whereas CYP2C19*9 to CYP2C19*15
were reported by direct sequencing of the genomic DNA
from lymphoblastoid cell lines8 represented by Caucasians,
Asians and Africans. CYP2C19*16 was reported in a
Japanese subject demonstrating a lowered capacity to
hydroxylate mephobarbital9. CYP2C19*17 discovered
recently by direct sequencing of 5 flanking region was
shown to be the first mutant CYP2C19 allele associated
with ultrarapid drug metabolism10. CYP2C19*18 to
CYP2C19*21 were reported by direct sequencing of all
exons of CYP2C19 in Japanese subjects12. Different
research groups have reported variable cure rates in patients
possessing different CYP2C19 genotypes. Here we review
the effect of CYP2C19 phenotypes and genotypes on the
therapeutic response to proton pump inhibitors (PPIs)
based upon the clinical observations reported in the
literature.
Proton pump inhibitors (PPIs)
The major PPIs are OPZ, lansoprazole (LPZ),
pantoprazole (PPZ) and rabeprazole (RPZ). These are
used for the treatment of non ulcer dyspepsia (NUD),
reflux oesophagitis, gastroesophageal reflux disease
(GERD), Helicobacter pylori infection, gastric ulcers,

duodenal ulcers, prevention and treatment of non

steroidal anti inflammatory drugs associated damage,
treatment of Zollinger-Ellison syndrome and other hyper
acidic conditions. PPIs are prodrugs that, after oral
administration get absorbed into the systemic
circulation. After absorption, these enter the gastric
parietal cells from the plasma where in the acidic milieu
these are arranged non enzymatically to form active
sulphenamide derivatives which then bind covalently
to sulphhydryl groups of H+/K+ ATPase inhibiting these
irreversibly. All PPIs have a common pyridinyl sulphinyl
benzimidazole backbone. These are extensively
metabolized in the liver by CYPs to inactive
metabolites13. Although both CYP3A4 and CYP2C19
are involved in the metabolism of PPIs, the major
pathways are catalyzed by CYP2C19. OPZ is mainly
5-hydroxylated by CYP2C19 and partially by CYP3A4
to OPZ sulphone. LPZ is converted to 5-OH-LPZ by
CYP2C19 and to LPZ sulphone by CYP3A4. PPZ is
mainly converted to demethylated PPZ by CYP2C19
but a minor pathway to PPZ sulphone by CYP3A4 also
exist14. RPZ is mainly metabolized nonenzymatically
to RPZ thioether but minor pathways to demethylated
RPZ by CYP2C19 and RPZ sulfone by CYP3A4 also
exists14. Specifically, since CYP2C19 plays a major role
in the metabolism, studies have linked genetic
polymorphism of CYP2C19 with therapeutic response.
Genetic polymorphism of CYP2C19
Genetic polymorphism of CYP2C19 occurs with
varying frequency among different ethnic groups viz.,
15-22.5 per cent in Japanese 15,16, 12.6 per cent in

Fig. Schematic picture demonstrating CYP2C19 alleles. Nine exons are depicted in the boxes. CYP2C19*2 to CYP2C19*21 are shown with
the corresponding nucleotide change. CYP2C19*2 to CYP2C19*8 and CYP2C19*16 were discovered in the subjects who demonstrated
decreased ability to metabolize the probe drugs whereas CYP2C19*9 to CYP2C19*15 were discovered by direct sequencing of genomic
DNA from lymphoblastoid cell lines. CYP2C19*17 was discovered recently in ultra rapid metabolizers by direct sequencing of 5 flanking
region. CYP2C19*18 to CYP2C19*21 were discovered by direct sequencing of all exons of CYP2C19.

CHAUDHRY et al: CYP2C19 & RESPONSE TO PPIS

Koreans17, 13-20 per cent in Chinese11,12 per cent in

north Indians5, 14 per cent in south Indians18, 2.8-5.2
per cent in Africans19,20, 0.95 to 7 per cent in CaucasianEuropeans21,22, 2 per cent in African-Americans23, 2.42.6 per cent in Caucasian-Americans24,25 and 70 per cent
in Vanuatu islands of Melanesia26.
CYP2C19 genotypes and pharmacokinetics and
pharmacodynamics of PPIs
It has been observed that usual doses of PPIs in
EMs could not attain plasma levels that are sufficient
to cause acid inhibitory effect. Hence, intragastric pH
is lower in EMs. On the other hand, duration of exposure
to high plasma concentration of PPIs is longer in PMs
and the proton pumps in parietal cells remain inactivated
for longer period resulting in higher pH and a better
therapeutic outcome27-36.
Table I summarizes different studies correlating
pharmacogenetics of CYP2C19 with pharmacokinetics
and pharmacodynamics of OPZ, LPZ and RPZ in
various ethnic groups. The direct CYP2C19 gene dose
effect is evident from the significantly different plasma
area under curve (AUC) and half life values of OPZ,
LPZ and RPZ after oral administeration in three
CYP2C19 genotype groups. CYP2C19 normal
homozygotes demonstrated lowest, heterozygotes
intermediate and mutant homozygotes highest AUC and
plasma half life values of these PPIs. Varying plasma
concentrations and half lives of PPIs in different
CYP2C19 genotype groups lead to differences in
inhibition of the acid secretion from the gastric parietal
cells. Thus, intragastric pH after treatment with OPZ,
LPZ and RPZ differed significantly between three
CYP2C19 genotype groups. CYP2C19 normal
homozygotes demonstrated lowest, heterozygotes
intermediate and mutant homozygotes highest
intragastric pH values. Gastrin AUC values also
depended significantly on CYP2C19 genotypes.
CYP2C19 normal homozygotes demonstrated lowest,
heterozygotes intermediate and mutant homozygotes
highest gastrin AUC values. Thus, majority of
observations demonstrated that CYP2C19
pharmacogenetics influences the pharmacokinetics and
pharmacodynamics of PPIs. Thus, the proton pumps in
parietal cells are inactivated by higher concentration of
PPIs and for a longer time in CYP2C19 mutant
homozygotes resulting in a stronger acid inhibition and
higher intragastric pH. Hence, if CYP2C19 genotypes
are known prior to PPI based treatment, an optimal dose
can be prescribed in order to achieve a better therapeutic
outcome.

523

CYP2C19 genotypes in chemotherapy of H. pylori

H. pylori was discovered in the stomach of patients
with gastritis and peptic ulceration37. Eversince infection
of mucosa of stomach and duodenum by H. pylori has
been found to be associated with gastritis, gastric ulcers,
duodenal ulcers, gastric carcinoma and other upper
gastrointestinal disorders 38-40 . Different treatment
regimens are used to eradicate H. pylori but the best
results are achieved by triple therapy consisting of a
combination of two antibiotics [amoxicillin (AMC),
clarithromycin (CAM), tinidazole (TNZ) and
metronidazole (MNZ)] and one PPI 41. PPIs are an
important part of anti H. pylori therapy as these increase
the pH of the stomach to levels where the antibiotics
are stable and thus increase the bioavailability of
antibiotics42. OPZ is known to increase the concentration
of AMC in gastric juice43. OPZ per se demonstrated
anti H. pylori activity 44 . A relationship between
CYP2C19 genotypes and cure rates of H. pylori on
treatment with PPI based dual, triple and quadruple
therapy has been demonstrated in Orientals and
Caucasians (Table II).
CYP2C19 genotypes in PPI based dual eradication
therapy: Furuta et al45 treated H. pylori positive gastric
ulcer Japanese patients with 20 mg OPZ quaque die
(qd) for 8 wk and 500 mg AMC quarter in die (qid) for
first 2 wk and duodenal ulcer Japanese patients with 20
mg OPZ (qd) for 6 wk and 500 mg AMC (qid) for first
2 wk. They reported 29, 60 and 100 per cent H. pylori
eradication in normal homozygotes, heterozygotes and
mutant homozygotes, respectively. Higher cure rates
observed in mutant homozygotes were attributed to
higher plasma concentration of OPZ. Gastric pH was
found to be highest in mutant homozygotes,
intermediate in heterozygotes and least in normal
homozygotes. Stability and antibacterial activity of
AMC were maximum at high pH. High dose of OPZ
may thus be required to achieve high cure rates of H.
pylori infection in EMs who metabolize PPIs efficiently.
Therapy with 20 mg OPZ bis in die (bid) and 500 mg
AMC (qid) for 1 wk demonstrated 100 per cent
eradication in Japanese mutant homozygotes compared
to 40 and 42 per cent in normal homozygotes and
heterozygotes, respectively46. Therefore, anti H. pylori
effect of dual therapy is efficient in PMs and hence
suggests that CAM can be avoided for therapy of
CYP2C19 PMs. Furuta et al47 treated Japanese H. pylori
positive gastritis patients with 10 mg RPZ (bid) and
500 mg AMC ter in die (tid) for 2 wk. A significant
difference in cure rates among 3 genotypes viz., normal

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INDIAN J MED RES, JUNE 2008

Table I. CYP2C19 genotypes and response to proton pump inhibitors (PPIs)

PPI treatment

Parameter

CYP2C19 genotypes
*1/*1

*1/*X

*X/*X

20 mg OPZ (qd) x 1 day

(Japanese)

(n)
Intragastric pH
OPZ AUC
Gastrin AUC

5
2.14
421
1,568

4
3.3
1,403
1,470

6
4.47
5,109
2,386

20 mg OPZ (qd) x 7 days

(Japanese)

(n)
Intragastric pH

6
3.7

6
4.4

6
6.3

20 mg OPZ (qd) x 8 days

(Swedish Caucasians)

(n)
Intragastric pH
Gastrin AUC

6
3.6
0.119

6
5.7
0.301

2
6.2
0.333 & 0.291a

30 mg LPZ (qd) x 8 days

(Japanese)

(n)
Intragastric pH
LPZ AUC
T1/2 LPZ (h)

7
4.4
2,000
1

5
4.9
4,400
2.3

3
5.4
9,200
4.6

30 mg LPZ (qd) x 8 days

(Japanese)

(n)
LPZ AUC
Gastrin AUC
T1/2 LPZ (h)

5
1,700
1,617
1.2

5
2,900
2,384
1.5

5
6,600
3,576
3.9

30 mg LPZ (qd) x 1 day

(Chinese)

(n)
LPZ AUC
T1/2 LPZ (h)

9
3,230
1.96

9
11,050
4.21

30 mg LPZ (qd) x 7 days

(Japanese)

(n)
Intragastric pH
Day time
Night time

3.1
1.8

3.5
2.2

6.2
5.9

Ref.
27

28
29

30

31

32

33

20 mg RPZ (bid) x 3 days

20 mg RPZ (qd) x 4th day
(Taiwanese)

(n)
RPZ AUC
Gastrin AUC
T1/2 RPZ (h)

6
1,619
1,940
1.05

10 mg RPZ (qd) x 8 days

(Japanese)

(n)
RPZ AUC
Gastrin AUC
T1/2 RPZ (h)

5
390
1,602
0.9

5
650
2,518
1.4

5
1,480
3,205
2.1

10 mg RPZ (qd) x 1 day

(Japanese)

(n)
Intragastric pH
RPZ AUC
Gastrin AUC
T1/2 RPZ (h)

5
2.88
228
1,349
0.66

6
3.12
306
1,443
0.90

4
4.45
696
1,903
1.69

20 mg RPZ (qd) x 8 days

(Japanese)

(n)
Intragastric pH

5
3.8

6
4.5

4
6.1

6
5,601
3,625
3.03

34

31

35

36

a-Individual values are given; AUC of OPZ, LPZ and RPZ = ng.h/mL; AUC of gastrin = pmol or pg.h/mL
LPZ, Lansoprazole; OPZ, omeprazole; RPZ, rabeprazole; AUC, area under curve; *1/*1-normal homozygotes, *1/*X heterozygotes and
*X/*X-mutant homozygotes; n, is sample size.

homozygotes (61%), heterozygotes (92%) and mutant

homozygotes (94%) was observed. The non eradicated
patients consisting of normal homozygotes and
heterozygotes when treated with a high RPZ dose dual
therapy consisting of 10 mg RPZ (qid) and 500 mg AMC

(qid) for 2 wk demonstrated 100 per cent H. pylori

eradication. Thus, H. pylori eradication with RPZ also
depends on CYP2C19 genotypes. H. pylori infected
Japanese normal homozygotes were successfully treated
with high doses of dual therapy with 40 mg OPZ (tid)

CHAUDHRY et al: CYP2C19 & RESPONSE TO PPIS

525

Table II. CYP2C19 genotypes and eradication of H. pylori using different proton pump inhibitor (PPI) based therapies
Doses
OPZ 20 mg qd
AMC 500 mg qid

8 wk
2 wk

OPZ 20 mg bid
AMC 500 mg qid

1 wk

RPZ 10 mg bid
AMC 500 mg tid

1 wk

OPZ 20 mg bid
AMC 400 mg qid
CAM 200 mg qid
OPZ 20 mg bid or
LPZ 30 mg bid
AMC 500 mg tid
CAM 200 mg tid

1 wk

1 wk

OPZ 20 mg bid
AMC 1000 mg bid
CAM 500 mg bid

1 wk

*X/*X

Ref.

Japanese

Dual

(n=28)
29

(n=25)
60

(n=9)
100

44

Japanese

Dual

(n=10)
40

(n12)
42

(n=4)
100

45

Japanese

Dual

(n=33)
61

(48)
92

(16)
94

46

Japanese

Triple

(n=20)
75

(n=26)
88

(n=11)
100

45

Japanese

Triple

(n=88)
73

(n=127)
92

(n=46)
98

50

Japanese

Triple

(n=33)
73

(35)
74

(12)
83

51

Italian Caucasian

Triple

(n=116)
60

(n=25)
84

(n=2)
100

52

(n=86)

(n=45)

57

80

97.8

5 wk

or
LPZ 30 mg bid
AMC 1000 mg bid
CAM 250 mg bid
MNZ 400 mg bid

Therapy

1 wk

LPZ 30 mg bid
AMC 750 mg bid
CAM 400 mg bid

LPZ 30 mg bid
AMC 1000 mg bid
CAM 250 mg bid
MNZ 400 mg bid

*1/*1

% eradication rates
*1/*X

Ethnic group

German
x 5 days

Caucasian

Quadruple

3 days

AMC, Amoxicillin; CAM, clarithromycin; LPZ, lansoprazole; MNZ, metronidazole; OPZ, omeprazole; RPZ, rabeprazole;*1 *1 -normal
homozygotes, *1/*X -heterozygotes and *X/*X -mutant homozygotes; n, is sample size; qd, quaque die; bid, bis in die; qid, quarter in die;
tid, ter in die.

and 750 mg AMC (tid) after failure to eradicate H. pylori

with usual PPI based triple therapy48. Triple therapy with
OPZ, AMC and CAM is not necessary in PMs as dual
therapy with OPZ and AMC is highly efficient. CAM
increases the plasma concentration of PPIs, since it
inhibits CYP2C19 and CYP3A4, resulting in higher
cure rates in EMs. Plasma concentration of OPZ in
healthy Japanese PMs following CAM and OPZ coadministration was 34 times higher than normal
homozygote EMs49. Contrary to above observations,
Miyoshi et al50 after treatment of H. pylori positive
Japanese patients with OPZ 20 mg (bid) and AMC 500
mg (tid) for 14 days demonstrated a statistically non
significant difference in eradication i.e., 73.9, 68.8 and
83.3 per cent in normal homozygotes, heterozygotes
and mutant homozygotes, respectively. Also on

treatment with RPZ 10 mg (bid) and AMC 500 mg (tid)

for 14 days, a statistically non significant difference in
eradication i.e., 71.4, 77.1 and 73.3 per cent in normal
homozygotes, heterozygotes and mutant homozygotes,
respectively was observed50.
CYP2C19 genotypes in PPI based triple eradication
therapy: Using a triple therapy of 20 mg OPZ (bid),
500 mg AMC (qid), 200 mg CAM (qid) for 1 wk, 100
per cent eradication was achieved in PMs compared to
75 and 88 per cent in normal homozygotes and
heterozygotes, respectively46. Two hundred sixty one
H. pylori positive Japanese patients were prescribed
triple therapy [20 mg OPZ or 30 mg LPZ (bid), 500 mg
AMC (tid) and 200 mg CAM (tid) for 1 wk] and 73, 92
and 98 per cent eradication was observed in normal

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INDIAN J MED RES, JUNE 2008

homozygotes, heterozygotes and mutant homozygotes,

respectively51 . Noneradicated group consisted of 69 per
cent normal homozygotes, 28 per cent heterozygotes
and 3 per cent mutant homozygotes who were then
treated with higher doses of dual therapy depending on
CYP2C19 genotypes. Normal homozygotes and
heterozygotes were retreated with 30 mg LPZ (qid) and
500 mg AMC (qid) whereas the mutant homozygotes
with 30 mg LPZ (bid) and 500 mg AMC (qid). The
final eradication rate of 99.6 per cent was achieved51.
Therefore, by adjusting the doses according to
CYP2C19 genotypes and selecting the antibiotic to
which the bacteria is sensitive, dual therapy is sufficient
to cure H. pylori infection. Kawabata et al52 treated 80
H. pylori positive Japanese patients with triple therapy
consisting of 30 mg LPZ (bid), 750 mg AMC (bid) and
400 mg CAM (bid) and observed 73, 74 and 83 per
cent H. pylori eradication in normal homozygotes,
heterozygotes and mutant homozygotes, respectively.
Similar observations were reported in Caucasians.
Sapone et al53 reported the first pharmacogenomic study
with respect to CYP2C19 genotypes and H. pylori
eradication in Italian Caucasians. Using a triple therapy
of 20 mg OPZ (bid), 1000 mg AMC (bid) and 500 mg
CAM (bid) for 1 wk, 60, 84 and 100 per cent eradication
was observed in normal homozygotes, heterozygotes
and mutant homozygotes, respectively53. Fifty patients
in whom H. pylori was not eradicated were either normal
homozygotes (92%) or heterozygotes (8%)53. In contrast
to above observations, some studies demonstrated no
association between CYP2C19 polymorphism and
eradication of H. pylori. No correlation was observed
between CYP2C19 genotypes and eradication of H.
pylori after treatment with LPZ 30 mg (bid), AMC 1000
mg (bid) and CAM 400 mg (bid) for 7 days as 100, 96
and 100 per cent eradication was observed in Japanese
normal homozygotes, heterozygotes and mutant
homozygotes, respectively54. Similarly, after treatment
with RPZ 10 mg (bid), AMC 1000 mg (bid) and CAM
400 mg (bid) for 7 days 100, 95 and 100 per cent
eradication was observed in Japanese normal
homozygotes, heterozygotes and mutant homozygotes,
respectively indicating that CYP2C19 polymorphism
did not influence H. pylori eradication54. Inaba et al55
treated H. pylori positive Japanese patients with OPZ
20 mg (bid), AMC 500 mg (tid) and CAM 200 mg (tid)
for 7 days and demonstrated a statistically non
significant difference in eradication i.e., 76.2, 88.9 and
90 per cent in normal homozygotes, heterozygotes and
mutant homozygotes, respectively. Similarly after
treatment with LPZ 30 mg (bid), AMC 500 mg (tid)

and CAM 200 mg (tid) for 7 days a statistically non

significant difference in eradication i.e., 90, 89.7 and
88.9 per cent in normal homozygotes, heterozygotes
and mutant homozygotes, respectively was observed.
Hokari et al56 categorized H. pylori positive Japanese
patients according to drug prescription into 3 groups.
Group 1 was prescribed 1 wk therapy consisting of RPZ
10 mg (qd), AMC 750 mg (bid) and CAM 200 mg (bid).
Group 2 was prescribed 1 wk therapy consisting of RPZ
10 mg (bid), AMC 750 mg (bid) and CAM 200 mg (bid).
Group 3 was prescribed 1 wk therapy consisting of RPZ
20 mg (bid), AMC 750 mg (bid) and CAM 200 mg (bid).
Data from EMs and PMs were analyzed collectively
from the 3 groups. EMs and PMs demonstrated a non
significant difference (86 vs 77%) in eradication of H.
pylori. Dojo et al57 divided H. pylori positive Japanese
patients into 2 treatment groups randomly. Group 1 after
treatment with 1 wk triple therapy consisting of OPZ
20 mg (bid), AMC 750 mg (bid) and CAM 400 mg (bid)
demonstrated non significant eradication of 73.3, 86.1
and 85 per cent in normal homozygotes, heterozygotes
and mutant homozygotes, respectively. Group 2 after
treatment with 1 wk triple therapy consisting of RPZ
20 mg (bid), AMC 750 mg (bid) and CAM 400 mg (bid)
demonstrated non significant eradication of 81, 82.9
and 87.5 per cent in normal homozygotes, heterozygotes
and mutant homozygotes, respectively; thus
demonstrating no association of CYP2C19 genetic
polymorphism with H. pylori eradication.
CYP2C19 genotypes in PPI based quadruple
eradication therapy: Effect of CYP2C19 polymorphism
was studied in German Caucasians using qudruple
therapy for H. pylori eradication consisting of 30 mg
LPZ (bid), 1000 mg AMC (bid), 250 mg CAM (bid)
and 400 mg MNZ (bid) for 5 days. Heterozygotes and
mutant homozygotes demonstrated significantly higher
eradication (97.8%) compared with normal
homozygotes (80.2%)58. LPZ serum trough steady state
concentrations were also significantly different viz.,
78.1, 135 and 766 ng/ml in normal homozygotes,
heterozygotes and mutant homozygotes, respectively.
Hence, they concluded that the eradication of H. pylori
is dependent on CYP2C19 genotypes when standard
doses of LPZ are used in Caucasians58. Results from
these studies emphasize that EMs (normal homozygotes
and heterozygotes) compared to PMs (mutant
homozygotes) should be prescribed higher doses of PPIs
in order to achieve optimal eradication of H. pylori.
Higher eradication rates observed in PMs compared to
EMs is due to the impaired metabolism of PPIs in PMs.
This results in the exposure of proton pumps in parietal

CHAUDHRY et al: CYP2C19 & RESPONSE TO PPIS

cells to higher concentration of PPIs and for longer

duration in PMs (mutant homozygotes). This leads to
higher intragastric pH at which the antibiotics are stable
and thus increase the bioavailability of the antibiotics
in PMs42. OPZ is known to increase the concentration
of AMC in the gastric juice 43, this effect will be
pronounced in PMs. Since OPZ per se demonstrates
anti H. pylori activity44, this action will also be more
pronounced in PMs. Hence, if CYP2C19 genotypes are
known prior to PPI based therapy, an optimal dose can
be prescribed in order to achieve a better therapeutic
outcome.
CYP2C19 and H. pylori eradication in north Indian
patients: Since the frequency of CYP2C19 EMs is
88 per cent in north Indians 59, approximately 880
million people in this country are expected to be
CYP2C19 EMs, and they should be treated with
increased doses of PPIs compared to PMs to achieve
optimal recovery. However, correlation between
CYP2C19 phenotypes, genotypes, eradication of H.
pylori and chemotherapy of gastritis has not been
studied in north Indians. Since this correlation is of
utmost importance for patient care, a study on the
role of CYP2C19 phenotypes and genotypes in the
eradication of H. pylori and chemotherapy of gastritis
in north Indians was initiated in our laboratory.
Ninety one H. pylori positive north Indian patients
were phenotyped and genotyped for CYP2C19 by
high performance liquid chromatography (HPLC) and
polymerase chain reaction-restriction fragment length
polymorphism (PCR-RFLP), respectively. Initial H.
pylori eradication therapy consisted of 20 mg OPZ
(bid), 750 mg AMC (bid) and 500 mg TNZ (bid) for
7 days. Noneradicated EMs were retreated with dual
therapy consisting of 40 mg OPZ (bid) and 500 mg
AMC (qid) for 14 days whereas PMs were retreated
with 20 mg OPZ (bid) and 500 mg AMC (qid) for 14
days. After initial triple therapy EMs and PMs
demonstrated 37 and 92 per cent eradication,
respectively. Non eradicated EMs retreated with 40
mg OPZ (bid) and 500 mg AMC (qid) dual therapy
demonstrated 90 per cent eradication. Non eradicated
PMs retreated with 20 mg OPZ (bid) and 500 mg
AMC (qid) demonstrated 100 per cent eradication,
thus demonstrating a direct correlation of CYP2C19
phenotypes and genotypes with eradication of H.
pylori in north Indians59.
The conflicting data in the literature about the role
of pharmacogenetics of CYP2C19 in the eradication of
H. pylori may be due to a variety of other factors that

527

determine drug responses in addition to the

pharmacogenetics of CYP2C19 viz., age, sex, nutritional
status, liver and kidney function, concomitant diseases
and medications, pharmacogenetics of CYP3A4 and
interleukin-1 (IL-1) genetic polymorphism. Sapone
et al53 analyzed the combined effect of CYP2C19 and
CYP3A4 polymorphisms on eradication of H. pylori in
Italian Caucasians using 20 mg OPZ (bid), 1000 mg
AMC (bid) and 500 mg CAM (bid) for 7 days. The
reason for this analysis was that PPIs are extensively
metabolized by CYP2C19 but also metabolized by
CYP3A4 to a lesser extent. CYP2C19 heterozygote
patients who were also heterozygotes for CYP3A4*1B,
CYP3A4*2 and CYP3A4*3 demonstrated 100 per cent
eradication. Thus, there may be a possibility of existence
of a positive synergism between the pharmacogenetics
of CYP2C19 and CYP3A4 in eradication of H. pylori.
IL-1 C-511T genetic polymorphism also influences the
effect of CYP2C19 pharmacogenetics on the eradication
of H. pylori. IL-1 is a proinflammatory cytokine with
multiple biological effects, including potent inhibition
of gastric acid secretion. It is 100-fold more potent
inhibitor of gastric acid secretion than PPIs and is highly
expressed in the gastric mucosa of H. pylori infected
patients. Since the antibiotics used for eradicating H.
pylori are acid sensitive, IL-1 genetic polymorphism
can also affect the anti H. pylori therapy. After treatment
of Japanese with 750 mg AMC (bid) and 200 mg CAM
(bid) together with either 20 mg OPZ (bid), 30 mg LPZ
(bid) or RPZ 10 mg (bid) 78, 78 and 90 per cent
eradication was observed in CYP2C19 normal
homozygotes, heterozygotes and mutant homozygotes,
respectively. In IL-1 -511 C/T or T/T genotype (low
acid secretion) group, there was no statistically
significant difference in eradication among three
CYP2C19 genotypes. In contrast, in IL-1 -511 C/C
(normal acid secretion) group, the eradication rate
among CYP2C19 mutant homozygotes (93.3%) was
significantly higher than CYP2C19 normal
homozygotes (60%) and heterozygotes (63.6%).
Therefore, IL-1 genetic polymorphism in conjunction
with CYP2C19 genetic polymorphism could also affect
the eradication rates of H. pylori60. Studying the genetic
polymorphisms of CYP2C19, CYP3A4 and IL-1 and
also analysis of other confounding factors together in
different populations may further enhance the
understanding of the role of CYP2C19 polymorphism
in the chemotherapy of H. pylori eradication.
CYP2C19 genotypes in treatment of gastroesophageal
reflux disease (GERD): Cure rates for GERD differ

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significantly in Japanese patients with different

CYP2C19 genotypes. Cure rates in normal
homozygotes, heterozygotes and mutant homozygotes
after 8 wk treatment with 30 mg LPZ (qd) were 46, 68
and 85 per cent, respectively. Lowest cure rate observed
in normal homozygotes was attributed to low plasma
LPZ concentrations (312, 440 and 745 ng/ml in normal
homozygotes, heterozygotes and mutant homozygotes,
respectively)61. Kawamura et al62 treated 88 Japanese
patients suffering from erosive reflux oesophagitis with
30 mg LPZ (qd) for 8 wk and observed 77, 95 and 100
per cent cure rates in normal homozygotes,
heterozygotes and mutant homozygotes, respectively,
suggesting that CYP2C19 genotypes influence the
therapeutic outcome.
CYP2C19 genotypes in treatment of duodenal ulcers:
A Japanese heterozygote patient with recurrent ulcer
responded to 60 mg LPZ/day instead of 30 mg LPZ/
day63. After treatment with 60 mg LPZ/day, pH of > 3
was maintained for 99.8 per cent time as against 88.3
per cent after treatment with 30 mg LPZ/day 62. H.
pylori associated refractory duodenal ulcer was cured
with 40 mg OPZ (tid) and 750 mg AMC (tid) after
failure to cure the ulcer with usual PPI based triple
therapies in normal homozygote Japanese 47. Results
from these studies emphasize that EMs (normal
homozygotes and heterozygotes) compared to PMs
(mutant homozygotes) should be prescribed higher
doses of PPIs in order to achieve optimal therapeutic
outcome against GERD, reflux oesophagitis as well
as duodenal ulcers.
Conclusion
Available data demonstrate that CYP2C19
pharmacogenetics influences the pharmacokinetics of
PPIs. CYP2C19 mutant homozygotes demonstrate
increased plasma concentration of PPIs and hence
highest inhibition of proton pumps. CYP2C19 normal
homozygotes, heterozygotes and mutant homozygotes
demonstrated lowest, intermediate and highest H. pylori
eradication, respectively using different therapies.
Hence, CYP2C19 genotyping prior to treatment can help
to optimize the PPI dose to achieve a better therapeutic
outcome. This shall help in the better management of
patients of GERD, gastritis, gastric and duodenal ulcers.
Acknowledgment
The first author (ASC) thanks Indian Council of Medical
Research, New Delhi for the award of research fellowship and the
last author (KKK) to Department of Biotechnology for funding
the project.

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Reprint requests: Dr K.K. Kohli, Department of Biochemistry, Postgraduate Institute of Medical Education & Research
Chandigarh 160 012, India
e-mail: kris_kohli2003@yahoo.com