CYP2C19 genotype and phenotype determined with omeprazole in patients with acid-related disorders with and without Helicobacter pylori infection.
BACKGROUND
Omeprazole is to a major extent metabolized by cytochrome P450 isozyme CYP2C19. The aims of this study were to compare the phenotype of CYP2C19 determined by omeprazole with the genotype and to determine the effect of Helicobacter pylori infection on the metabolism of omeprazole.


METHODS
One-hundred and forty-three Caucasian patients with acid-related disorders assessed with a combination of gastrointestinal symptoms and upper endoscopic findings were given 20 mg omeprazole orally. Three hours after intake, omeprazole and 5-hydroxyomeprazole plasma concentrations were determined with high-performance liquid chromatography, and the phenotype for metabolic capacity was expressed as metabolic ratio (MR). Genotyping of defect alleles (CYP2C19*2 and *3) was performed by polymerase chain reaction amplification. One hundred eleven patients were tested after the first dose of omeprazole and 32 patients after repetitive administration (median time, 30 days). H. pylori serology was determined with enzyme-linked immunosorbent assay at the time of phenotyping.


RESULTS
Genotypically, 2.8% had two mutated alleles and were poor metabolizers (PM), and 22.4% were heterozygous extensive metabolizers (EM). Among the 111 patients who received the first omeprazole dose, 4 patients had MR >5--that is, belonged to the PM phenotype. Two of these had PM genotype (both CYP2C19*2/*2), and two had an EM genotype (CYP2C19*11*1 and *1/*3), indicating that they have still unidentified mutations. In the heterozygous EM group the mean MR was higher in patients who had been on continued omeprazole treatment than in those given the first dose (5.7 versus 2.5, P = 0.02). There were no significant differences in MR and omeprazole concentrations between H. pylori-negative (43%) and -positive (57%) patients.


CONCLUSIONS
In all but two patients with probable unidentified mutations there was agreement between the CYP2C19 phenotype determined by omeprazole and the genotype. The metabolism of omeprazole in patients with acid-related disorders is genetically determined and without relation to H. pylori infection.
Sagar
M
M
Dept. of Surgery, Clinical Research Center, Karolinska Institute, Huddinge Hospital, Sweden.
Seensalu
R
R
Tybring
G
G
Dahl
M L
ML
Bertilsson
L
L
D000897:Anti-Ulcer Agents / Q000378:metabolism* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy / Q000201:enzymology*; D005838:Genotype; D016481:Helicobacter Infections / Q000201:enzymology*; D016480:Helicobacter pylori; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D009853:Omeprazole / Q000378:metabolism* / Q000627:therapeutic use; D010437:Peptic Ulcer / Q000188:drug therapy / Q000201:enzymology*; D010641:Phenotype; D016133:Polymerase Chain Reaction
D000897:Anti-Ulcer Agents; 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