Gastroenterology

Gastroenterology

Volume 119, Issue 3, September 2000, Pages 670-676
Gastroenterology

Alimentary Tract
Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism☆,☆☆

https://doi.org/10.1053/gast.2000.16515Get rights and content

Abstract

Background & Aims: Omeprazole is metabolized by cytochrome P450 (CYP2C19). The activity of this enzyme is polymorphic, with incidences of poor metabolizers (PMs), heterozygous extensive metabolizers (EMs), and homozygous EMs in white populations of 3%, 30%, and 67%, respectively. The importance of the CYP2C19 polymorphism for the effects of omeprazole on intragastric pH and plasma gastrin concentrations has been investigated. Methods: Twenty-five white patients were genotyped for CYP2C19 by allele-specific polymerase chain reaction amplification, and their Helicobacter pylori status was assessed by serology and with immunoblot analysis. Intragastric pH was monitored over 24 hours, and meal-stimulated plasma gastrin concentration was measured over 4 hours (AUC 4h) before (day 0) and during (day 8) treatment with 20 mg omeprazole once daily. Results: Eleven patients were homozygous for the wild-type allele (wt/wt), 12 were heterozygous EMs (wt/mut), and 2 were PMs (mut/mut). Median (95% confidence interval) 24-hour intragastric pH in the heterozygous EM group was 5.5 (range, 5.1–5.9) compared with 3.1 (range, 2.7–3.6) in homozygous EMs (P < 0.0001) at day 8. The percentage of time with intragastric pH > 4 at day 8 was significantly higher in the wt/mut than wt/wt group (72.4% vs. 37.1%; P < 0.0001). H. pylori status had less influence than CYP2C19 on intragastric acidity. Omeprazole treatment increased meal-stimulated plasma gastrin concentrations from day 0 to day 8 in the homozygous EMs and heterozygous EMs by 16% (NS) and 157% (P = 0.002), respectively. In heterozygous EMs, the gastrin increase was more pronounced in the H. pylori–positive group (226%) than H. pylori–negative group (80%; P = 0.02). Conclusions: The effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism in patients with acid-related disorders.

GASTROENTEROLOGY 2000;119:670-676

Section snippets

Study population

Twenty-five white Swedish patients with endoscopically proven acid-related disease participated in the study. Seventeen patients had nonactive ulcers, 7 had gastroesophageal reflux disease, and 1 had erosive gastritis. Exclusion criteria were pretreatment with antisecretory drugs, severe concomitant disease, and a history of gastric surgery. Eleven patients were recruited randomly from an outpatient clinic to be genotyped and phenotyped for CYP2C19, for gastric secretory tests, and for H. pylori

CYP2C19 genotypes and phenotypes

The effect of omeprazole treatment on intragastric acidity and plasma gastrin was evaluated before and during treatment in all 25 patients phenotyped and genotyped for CYP2C19. The patients were grouped according to their CYP2C19 genotype and with respect to H. pylori serology. Eleven patients were homozygous EMs (wt/wt, i.e., CYP2C19*1/*1); 12 were heterozygotes (wt/mut, i.e., CYP2C19*1/*2); and 2 were PM, homozygous for a mutated allele (mut/mut, i.e., CYP2C19*2/*2). The mean MR for each

Discussion

We show that short-term oral treatment with 20 mg omeprazole daily in a group of heterozygous EMs (with respect to CYP2C19) increased 24-hour intragastric pH (pH 5.5) significantly more than in a group of normal, homozygous EMs (pH 3.1). Plasma gastrin concentrations increased by 157% compared with 16%, respectively. The 2 PMs recruited to the study showed a sustained effect of omeprazole, with intragastric pH of >5 throughout the 24-hour monitoring period (Figure 2C). Also, the pH profile over

Acknowledgements

The authors thank Prof. Lars Engstrand for the immunoblot analysis.

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    ☆

    Address requests for reprints to: Rein Seensalu, M.D., Department of Medicine, St Görans Sjukhus AB, S-112 81 Stockholm, Sweden. e-mail: [email protected]; fax: (46) 8-58701921.

    ☆☆

    Supported by the Swedish Medical Research Council (3902), EU Biomed 2 (BMH4-CT96-0291), and Karolinska Institutet.

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