Omeprazole Therapy and CYP2C19 Genotype

Laura Dean, MD1

Created: October 1, 2012; Updated: March 8, 2016.

Introduction
Omeprazole blocks the secretion of gastric acid and belongs to the drug class of proton
pump inhibitors. It is used to treat gastroesophageal reflux disease (GERD), gastric ulcers,
duodenal ulcers, erosive esophagitis, and other acid-related disorders. It is also used in the
treatment of hypersecretory conditions, such as Zollinger-Ellison syndrome, and is used
in combination with antibiotics to eradicate Helicobacter pylori (H. pylori) infection (1).
CYP2C19 is the principal enzyme that metabolizes omeprazole to inactive metabolites.
Approximately 3% of Caucasians and 15 to 20% of Asians have reduced or absent
CYP2C19 enzyme activity (“poor metabolizers”). In these individuals, standard doses of
omeprazole may lead to higher exposure to the drug and improved treatment outcomes
(2). In contrast, individuals with increased CYP2C19 activity (“ultrarapid metabolizers”)
may have an insufficient response to treatment as the active drug is inactivated at a faster
rate.
The FDA-approved drug label for omeprazole states that a dose reduction should be
considered in the Asian population, particularly for the maintenance of healing of erosive
esophagitis (1). The Pharmacogenetics Working Group of the Royal Dutch Association for
the Advancement of Pharmacy (KNMP) has published dose alterations based on
CYP2C19 genotype. For CYP2C19 poor metabolizers, they do not recommend altering
the dose; however for ultrarapid metabolizers, they recommend being extra alert to an
insufficient response to treatment. For the eradication of H. pylori in ultrarapid
metabolizers, they recommend increasing the dose of omeprazole by 100–200%, and to
consider the same dose increase for other conditions (see Table 1) (3, 4).

1 NCBI; Email: dean@ncbi.nlm.nih.gov.

NLM Citation: Dean L. Omeprazole Therapy and CYP2C19 Genotype. 2012 Oct 1 [Updated
2016 Mar 8]. In: Pratt V, McLeod H, Dean L, et al., editors. Medical Genetics Summaries
[Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-.

All Medical Genetics Summaries content, except where otherwise noted, is licensed under a
Creative Commons Attribution 4.0 International (CC BY 4.0) license which permits copying,
distribution, and adaptation of the work, provided the original work is properly cited and any
changes from the original work are properly indicated. Any altered, transformed, or adapted
form of the work may only be distributed under the same or similar license to this one.
2 Medical Genetics Summaries

Table 1. CYP2C19 phenotypes and the therapeutic recommendations for omeprazole therapy, adapted from
the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy
(KNMP).
Phenotype Phenotype details Examples of Therapeutic (dose)
diplotypes recommendations for
omeprazole
Ultrarapid metabolizer Normal or increased *17/*17 Be extra alert to insufficient
CYP2C19 activity response. For the eradication of
H. pylori, increase dose by 100–
200%.
For other conditions, consider
dose increase by 100–200%.
Extensive metabolizer Normal CYP2C19 *1/*1 No recommendations
activity
Intermediate Decreased CYP2C19 *1/*2 No recommendations
metabolizer activity *1/*3
*2/*17
*3/*17
Poor metabolizer Markedly reduced or *2/*2 No recommendations
absent CYP2C19 *2/*3
activity *3/*3
Good quality evidence supports the dose recommendations for poor and intermediate metabolizers;
moderate quality evidence supports the dose recommendations for ultrarapid metabolizers.
Table is adapted from Swen J.J., Nijenhuis M., de Boer A., Grandia L. et al. Pharmacogenetics: from bench to
byte - an update of guidelines. Clinical pharmacology and therapeutics. 2011;89(5):662–73 (3).

Drug class: Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are inhibitors of gastric acid secretion that are used in the
treatment of stomach-acid related disorders. PPIs are also used to prevent and treat ulcers
associated with nonsteroidal anti-inflammatory drugs (NSAIDs), and can be used in
combination with antibiotics to eradicate H. pylori infection.
Six PPIs are currently FDA-approved for clinical use: esomeprazole, dexlansoprazole,
lansoprazole, omeprazole, pantoprazole, and rabeprazole. All PPIs are similarly potent at
inhibiting gastric acid secretion and are thought to be similarly efficacious (5, 6).
PPIs are metabolized and inactivated by a number of CYP enzymes, including CYP2C19,
which has a principal role in the metabolism of omeprazole. The increased function
CYP2C19*17 variant allele may enhance PPI clearance (7) resulting in less active PPI
available to inhibit gastric acid secretion. In contrast, the CYP2C19*2 loss-of-function
allele is associated with decreased PPI clearance, resulting in more active PPI available
and enhanced treatment. For several PPIs, including omeprazole and lansoprazole, higher
drug levels in patients with low or absent CYP2C19 activity have been associated with
increased drug efficacy and improved treatment outcomes (2, 8).
Omeprazole Therapy and CYP2C19 Genotype 3

Drug: Omeprazole
Omeprazole was the first PPI to be introduced to the US market in 1989. Today,
omeprazole is one of the PPIs that are available both as prescription and over-the-counter
(OTC) medications.
In adults, omeprazole is used in the treatment of ulcers (gastric and duodenal), GERD,
and to maintain healing of erosive esophagitis. Omeprazole is also used in the long-term
treatment of hypersecretory conditions such as Zollinger-Ellison syndrome, multiple
endocrine adenomas, and systemic mastocytosis. In children, omeprazole is used in the
treatment of GERD and erosive esophagitis (1).
The human stomach contains approximately one billion parietal cells that secrete
hydrochloric acid (HCl) into the gastric lumen. Gastric acid aids digestion by hydrolyzing
dietary protein and facilitating the absorption of calcium, iron, and vitamin B. Gastric
acid also helps maintain a sterile environment by suppressing the growth of bacteria (9).
Hydrogen ions (H+) are actively secreted in to the gastric lumen in exchange for
potassium ions (K+) via an H+/K+-ATPase, which is also known as a “proton pump”.
Located on the surface of gastric parietal cells, the proton pump controls the last step in
acid secretion, and by targeting this step, omeprazole and the other PPIs are able to
potently inhibit gastric acid secretion.
Omeprazole is metabolized and inactivated in the liver by the cytochrome P450 system.
CYP2C19 is the principal enzyme involved, although other enzymes such as CYP3A4 may
also contribute. Omeprazole is metabolized to hydroxy and desmethyl metabolites, which
have no effect on gastric acid secretion (10).
Individuals with reduced CYP2C19 enzyme activity may experience twice the exposure to
omeprazole compared to individuals with normal enzyme function. This reduced enzyme
activity has a positive effect on clinical outcomes, and because PPIs are generally regarded
as safe drugs, especially in the short-term (less than 6 months), this can have a beneficial
effect without an increased risk of omeprazole toxicity (11, 12).
One study reported that when using omeprazole as part of the treatment to eradicate H.
pylori, success was achieved in all patients who had little or no CYP2C19 activity, but in
only 29% of patients who had “normal” CYP2C19 activity. Similar results were found in
another study that evaluated lansoprazole in the treatment of GERD: the cure rate was
85% for patients with little or no CYP2C19 activity, compared to 16% for patients with
normal CYP219 activity (13-15).
The FDA-approved drug label for omeprazole does not comment on dose adjustments
based on CYP2C19 status. However, guidelines from KNMP recommend that patients
with increased CYP2C19 activity (“ultrarapid metabolizers”) should receive an increased
dose of omeprazole for the eradication of H. pylori, and that an increased dose should be
considered for other indications (Table 1).
4 Medical Genetics Summaries

The long-term use of PPIs has been associated with several adverse effects. Daily
treatment with any PPI for longer than three years may lead to malabsorption of vitamin
B12, caused by hypochlorhydria. Because prolonged hypochlorhydria also increases the
risk of Clostridium difficile infection, and may increase the risk for osteoporosis-related
fractures, the FDA recommends that patients should use the lowest dose and shortest
duration of PPI therapy appropriate to the condition being treated (1).

Gene: CYP2C19
The cytochrome P450 superfamily (CYP) is a large and diverse group of enzymes that
form the major system for metabolizing lipids, hormones, toxins, and drugs. The CYP
genes are very polymorphic and can result in reduced, absent, or increased drug
metabolism.
The CYP2C19 enzyme contributes to the metabolism of a range of clinically important
drugs, such as antidepressants, benzodiazepines, and some of the PPIs, including
omeprazole.
CYP2C19 is highly polymorphic, as 35 variant star (*) alleles are currently catalogued at
the Human Cytochrome P450 (CYP) Allele Nomenclature Database (http://
www.cypalleles.ki.se/cyp2c19.htm). The CYP2C19*1 wild-type allele is associated with
normal enzyme activity and the “extensive metabolizer” phenotype (16).
The most common loss-of-function variant is CYP2C19*2, which contains a c.681G>A
variant in exon 5 that results in an aberrant splice site. This leads to the production of a
truncated and non-functioning protein. The CYP2C19*2 allele frequencies are ~15% in
Caucasians and Africans, and ~29–35% in Asians (17). “Intermediate metabolizers” carry
one copy of an allele that encodes reduced or absent function (e.g. *1/*2), whereas “poor
metabolizers” are homozygous or compound heterozygous for two loss-of-function alleles
(e.g., *2/*2, *2/*3).
Another commonly tested loss-of-function variant is CYP2C19*3, which contains a c.
636G>A variant in exon 4 that causes a premature stop codon. The CYP2C19*3 allele
frequencies are ~2–9% in Asian populations, but rare in other racial groups. Other loss-
of-function variants occur in less than 1% of the general population, and include
CYP2C19*4-*8 (17, 18).
In contrast to non-functional alleles, the CYP2C19*17 allele (c.-806C>T) is associated
with increased enzyme activity. Allele frequencies range from 3 to 21% across different
populations (19). Individuals who are homozygous for the *17 allele are known as
“ultrarapid metabolizers”, and it is this patient group who may benefit from an increased
dose of omeprazole. However, not all studies have identified a significant effect
of CYP2C19*17 on the metabolism of PPIs and treatment outcomes (15, 20, 21).
Omeprazole Therapy and CYP2C19 Genotype 5

Genetic Testing
Currently, the FDA does not provide recommendations about the use of CYP2C19 genetic
testing for omeprazole treatment (1).
Clinical genotyping tests are available for several CYP2C19 alleles, and a list of some test
providers is available at the Genetic Testing Registry (GTR) of the National Institutes of
Health: http://www.ncbi.nlm.nih.gov/gtr/tests/?term=1557[geneid].
Usually a patient’s result is reported as a diplotype, such as CYP2C19 *1/*1, and may also
include an interpretation of the patient’s predicted metabolizer phenotype (ultrarapid,
extensive, intermediate, or poor).
Table 1 summarizes common CYP2C19 phenotypes with recommendations developed by
the Pharmacogenetics Working Group of the Royal Dutch Association for the
Advancement of Pharmacy (KNMP).

Therapeutic Recommendations based on Genotype

This section contains excerpted1 information on gene-based dosing
recommendations. Neither this section nor other parts of this review contain the
complete recommendations from the sources.
2014 Statement from the US Food and Drug Administration (FDA): Asian Population:
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of
approximately four-fold was noted in Asian subjects compared with Caucasians. Dose
reduction, particularly where maintenance of healing of erosive esophagitis is indicated,
for Asian subjects should be considered.
Please review the complete therapeutic recommendations that are located here: (1)
2011 Summary of recommendations from the Pharmacogenetics Working Group of
the Royal Dutch Association for the Advancement of Pharmacy (KNMP): For
individuals who are ultrarapid metabolizers, an increase in the dose of omeprazole by
100–200% is recommended for the eradication of H.pylori, and the physician should be
extra alert to an insufficient response. For other conditions, the physician should remain
extra alert to an insufficient response, and consider a dose increase by 100–200%.
There are no therapeutic (dose) recommendations for individuals who are either poor or
intermediate metabolizers.
Please review the complete therapeutic recommendations that are located here: (3).

1 The FDA labels specific drug formulations. We have substituted the generic names for any
drug labels in this excerpt. The FDA may not have labelled all formulations containing the
generic drug.
6 Medical Genetics Summaries

Nomenclature
Common allele Alternative HGVS reference sequence dbSNP
name names reference
Coding Protein
identifier for
allele location
CYP2C19*2 681G>A NM_000769.1:c.681G>A NP_000760.1:p.Pro227= rs4244285
Pro227Pro
CYP2C19*3 636G>A NM_000769.1:c.636G>A NP_000760.1:p.Trp212Ter rs4986893
Trp212Ter
CYP2C19*17 -806C>T NM_000769.2:c.-806C>T Not applicable—variant rs12248560
occurs in a non-coding
region

Guidelines for the description and nomenclature of gene variations are available from the
Human Genome Variation Society (HGVS): http://www.hgvs.org/content/guidelines
Nomenclature for Cytochrome P450 enzymes is available from the Human Cytochrome
P450 (CYP) Allele Nomenclature Database: http://www.cypalleles.ki.se/

Acknowledgments
The author would like to thank Stuart A. Scott, Assistant Professor of Genetics and
Genomic Sciences, Icahn School of Medicine at Mount Sinai; and Mia Wadelius, Senior
Lecturer, Uppsala University; for reviewing this summary.

Version History
To view an earlier version of this summary (update: 18 March 2013), please click here.

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8 Medical Genetics Summaries

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