Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism.
OBJECTIVE
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.
Sagar
M
M
Center of Gastroenterology, Departments of Surgery and Medicine, Clinical Research Center, Huddinge University Hospital, Stockholm, Sweden.
Tybring
G
G
Dahl
M L
ML
Bertilsson
L
L
Seensalu
R
R
D000368:Aged; D000483:Alleles; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000097:blood*; D005838:Genotype; D016480:Helicobacter pylori / Q000302:isolation & purification; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000627:therapeutic use*; D009994:Osmolar Concentration; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000502:physiology*; D013272:Stomach Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000382:microbiology
D000897:Anti-Ulcer Agents; D005755:Gastrins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole