Pharmacogenomics of

Gastrointestinal Drugs: Focus on

Proton Pump Inhibitors
Lecture 11
 Introduction Omeprazole metabolism

• Proton pump inhibitors (PPIs), such as

omeprazole, lansoprazole, rabeprazole,
esomeprazole, and pantoprazole, are now
clinically used as the potent gastric acid
inhibitors for acid-related diseases, such as
peptic ulcer, gastroesophageal reflux diseases
(GERD), and Zollinger–Ellison syndrome.

• PPIs are also used for the eradication of H.

pylori with antimicrobial agents.

• Pharmacokinetics and pharmacodynamics of

PPIs are affected by the CYP2C19
polymorphism.
• Plasma concentration–time curves after oral dosing of 20 mg of omeprazole, 30
mg of lansoprazole, and 20 mg of rabeprazole for 8 days are also affected by
CYP2C19 genotype status.
Effect of CYP2C19 Polymorphism on GERD
Treatment by a PPI
• The cure rates of GERD attained by PPIs are varied in respond to the usual
standard dose of a PPI (e.g., 20 mg of omeprazole or 30 mg of lansoprazole).

• When 30 mg of lansoprazole was dosed in GERD patients positive for

mucosal breaks for 8 weeks, cure rates of mucosal breaks significantly
depended on CYP2C19 genotype status.

• The cure rate of mucosal breaks in the RM group was lowest, that in the IM
group came next, and that in the PM group was highest.
Effect of CYP2C19 Polymorphism on GERD
Treatment by a PPI
• Clinical Implications:

1. An increased dose of a PPI is recommended for the RM GERD patients

who are refractory to the treatment with a usual standard dose of a
PPI.

2. A more frequent daily dosing of lansoprazole (e.g., 30 mg four times a

day) can also achieve sufficient acid suppression in the RM genotype
group.

3. Histamine 2 (H2) receptor antagonists, such as famotidine, is not

affected by the CYP2C19 genotype status and superior to that of
lansoprazole in the RM patients. Therefore, concomitant treatment
with a PPI plus an H2 receptor antagonist appears to be another
therapeutic strategy for RM patients with GERD refractory to
treatment with a usual constant dose of a PPI alone.
The Effects of CYP2C19 Polymorphism on PPI-
Based Eradication Therapy of H. Pylori
• Current regimens for the eradication of H. pylori consist of a
PPI plus one or two antibacterial agents, such as amoxicillin,
clarithromycin, and metronidazole.

• The roles of PPIs in an H. pylori eradication therapy are as

follows:

1. PPIs make antibiotics more stable and bioavailable in the

stomach by raising intra-gastric pH to neutral levels.
Subsequently, increases the concentration of antibiotics,
such as amoxicillin, in the stomach.
2. Neutralization of intra-gastric pH levels allows H. pylori to
shift into the growth phase and thus they become more
sensitive to antibiotics, such as amoxicillin.
3. PPIs have an anti–H. pylori effect.
 Eradication Therapy for H. Pylori Infection in
Relation to CYP2C19 Polymorphism
• Dual Omeprazole/Amoxicillin Therapy • Triple PPI/Amoxicillin/Clarithromycin Therapy
The eradication rates for H. pylori by dual It was reported that eradication rates for H. pylori
omeprazole/amoxicillin (omeprazole 20 mg infection by a triple therapy with daily doses of
once daily plus amoxicillin 500 mg four omeprazole 40 mg or lansoprazole 60 mg, amoxicillin
times daily for 2 weeks) are approximately 1,500 mg, and clarithromycin 600 mg for 1 week
30% in the RMs, 60% in the IMs, and 100% were 72.7% in RMs, 92.1% in IMs, and 97.8% in PMs.
in the PMs.
Flow of standard versus tailored strategy of eradication of H.
pylori based on genotypes of CYP2C19 and H. pylori 23s rRNA

Abbreviations: AMPC, amoxicillin; LPZ, lansoprazole; CAM-S, clarithromycin-sensitive strain of H. pylori; CAM-R,
clarithromycin-resistant strain of H. pylori; RM, rapid metabolizer of CYP2C19; IM, intermediate metabolizer of CYP2C19; PM,
poor metabolizer of CYP2C19. Therefore, pharmacogenomics-based personalized eradication therapy is a useful strategy.