Omeprazole Pharmacogenetics - CYP2C19 Genetic Testing Gene2Rx

Drug Overview

Omeprazole is a widely used proton pump inhibitor (PPI) marketed under brand names such as Prilosec and Losec.

It is indicated for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, Helicobacter pylori infection (in combination therapy), and erosive esophagitis.

Omeprazole works by irreversibly inhibiting the H+/K+-ATPase enzyme (the proton pump) in gastric parietal cells, reducing gastric acid secretion and promoting mucosal healing.

Relevant Genes and Their Roles

The primary gene relevant to omeprazole metabolism is CYP2C19, which encodes an enzyme in the liver responsible for converting omeprazole into inactive metabolites. Variants in this gene can alter how quickly the drug is cleared from the body.

Genetic differences in CYP2C19 activity can lead to faster or slower metabolism of omeprazole. “Metabolizer” describes how active the enzyme is: ultrarapid/rapid metabolizers clear the drug quickly, while intermediate/poor metabolizers clear it more slowly.

Impact of Genetics on Drug Response

CYP2C19 genotype-based phenotypes influence omeprazole plasma levels and therapeutic effect. Ultrarapid and rapid metabolizers may have subtherapeutic drug concentrations and increased risk of treatment failure, whereas intermediate and poor metabolizers often have elevated drug levels, which can enhance efficacy but also raise the risk of side effects.

Expected Clinical Effects of Genetic Variation

Ultrarapid/Rapid Metabolizers

Effect on drug levels: Lower than average plasma concentrations.
Clinical consequence: Increased risk of therapeutic failure and persistent acid-related symptoms.
Side effects: Generally fewer side effects due to lower drug exposure; efficacy may be insufficient.

Normal Metabolizers

Effect on drug levels: Typical plasma concentrations.
Clinical consequence: Standard response; may require dose adjustments for H. pylori or severe esophagitis.
Side effects: Side effect profile as expected; low risk when dosed appropriately.

Intermediate Metabolizers

Effect on drug levels: Moderately increased plasma concentrations.
Clinical consequence: Enhanced efficacy and acid suppression; potential risk of dose-dependent toxicity during long-term use.
Side effects: Mild to moderate side effects (e.g., headache, abdominal discomfort) if standard doses are continued chronically.

Poor Metabolizers

Effect on drug levels: Significantly increased plasma concentrations.
Clinical consequence: High efficacy but elevated risk of dose-dependent adverse effects with prolonged therapy.
Side effects: Greater frequency of side effects (e.g., nausea, diarrhea, headache) on long-term dosing.

Indeterminate/Not available

Effect: Unknown impact on omeprazole metabolism.
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.

Dosing Guidelines

The following dosing guidelines are based on the available guidelines for omeprazole and CYP2C19 genotype from the CPIC.

CYP2C19 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Ultrarapid Metabolizer	Decreased plasma concentrations of PPIs compared with normal metabolizers; increased risk of therapeutic failure.	Increase starting daily dose by 100%; daily dose may be given in divided doses. Monitor for efficacy.
Rapid Metabolizer	Decreased plasma concentrations of PPIs compared with normal metabolizers; increased risk of therapeutic failure.	Initiate standard starting daily dose. Consider increasing dose by 50–100% for H. pylori infection or erosive esophagitis; daily dose may be divided. Monitor for efficacy.
Normal Metabolizer	Normal PPI metabolism; may be at increased risk of therapeutic failure compared with intermediate and poor metabolizers.	Initiate standard starting daily dose. Consider increasing dose by 50–100% for H. pylori infection or erosive esophagitis; daily dose may be divided. Monitor for efficacy.
Likely Intermediate Metabolizer	Likely increased plasma concentration of PPI compared with normal metabolizers; likely increased efficacy and potential toxicity.	Initiate standard starting dose. For chronic therapy (>12 weeks) with efficacy achieved, consider 50% dose reduction and monitor for continued efficacy.
Intermediate Metabolizer	Increased plasma concentration of PPI compared with normal metabolizers; increased efficacy and potential toxicity.	Initiate standard starting dose. For chronic therapy (>12 weeks) with efficacy achieved, consider 50% dose reduction and monitor for continued efficacy.
Likely Poor Metabolizer	Likely increased plasma concentration of PPI compared with normal metabolizers; likely increased efficacy and potential toxicity.	Initiate standard starting dose. For chronic therapy (>12 weeks) with efficacy achieved, consider 50% dose reduction and monitor for continued efficacy.
Poor Metabolizer	Increased plasma concentration of PPI compared with normal metabolizers; increased efficacy and potential toxicity.	Initiate standard starting dose. For chronic therapy (>12 weeks) with efficacy achieved, consider 50% dose reduction and monitor for continued efficacy.
Indeterminate	No CPIC guidance for this phenotype.	Initiate therapy with recommended starting dose.
Not available	No CPIC guidance for this phenotype.	Initiate therapy with recommended starting dose.

Alternative Treatment Options

The CPIC guideline focuses on dosing adjustments based on CYP2C19 phenotype and does not specify alternative drugs. Clinicians may consider other acid-suppressing therapies such as H2-receptor antagonists or switching to a different PPI if standard omeprazole dosing is ineffective.

Sources and References

CPIC – Guideline for Proton Pump Inhibitors and CYP2C19