The importance of the CYP2C19 polymorphism for disposition and effects of omeprazole treatment

Sammanfattning: CYP2C19, catalyzes the metabolism of omeprazole and several other drugs. About 3% of Caucasians are poor metabolizers (PM) of these drugs. The goal of this thesis was to evaluate the importance of CYP2C19 polymorphism for disposition and clinical effects of omeprazole treatment in healthy subjects and in patients with acid related disorders. The disposition of omeprazole was studied in three defined phenotypes of S-mephenytoin hydroxylation. After a single dose of 20 mg omeprazole, the area under the plasma concentration versus time curve (AUC) in PMs was five-fold higher than in heterozygous EM (het EMs), and 20 fold higher than in rapid EM (rapid EM; presumably homozygous wild type, but genotyping was not available at the time of this study). A similar pattern of AUCs was also found after eight daily doses of omeprazole. Gastrin secretion was also investigated in the same three groups. There was no significant change in the gastrin concentration in plasma in any of the three groups after a single dose of 20 mg omeprazole. A pronounced increase was seen in gastrin levels in both heterozygous EM and PM but not in rapid EMs after eight doses. After investigating the ratio of omeprazole/hydroxyomeprazole at different time points we subsequently suggested that this ratio determined with a single blood sample drawn at 3 hours after administration of the omeprazole might be used for phenotyping. One-hundred and forty-three Caucasian patients with acid related disorders were phenotyped with omeprazole and genotyped for defect CYP2C19 alleles (CYP2C19 '2and CYP2C19'3). We found that in all but two patients with probable unidentified mutations, there was an agreement between the CYP2C19 phenotype determined with omeprazole and the genotype, Twenty-five Caucasian patients with acid related disease were phenotyped with omeprazole, and genotyped for CYP2C19 with respect to defective alleles. Also, their H. pylori status was determined. Intragastric pH was monitored over 24 h and the area under the curve of meal stimulated plasma gastrin concentration was measured over 4h (AUC 4h) before (day 0) and during (day 8) treatment with 20 mg omeprazole once daily. There were no significant differences at day 0 in intragastric pH and plasma gastrin (AUC 4h) between the groups regardless of CYP2C19 genotype and H. pylori status. Treatment with 20 mg omeprazole daily induced significantly greater increase of both intragastric pH and plasma gastrin concentration in heterozygous EM compared to homozygous EM. H. pylori infection had an additional gastrin increasing effect but did not significantly influence intragastric acidity Serum gastrin, pepsinogen I and plasma chromogranin A were assessed in 180 patients with acid related disorder of different CYP2C19 genotype groups. In 71 patients on long-term treatment with orneprazole, serum gastrin and plasma chromogranin A concentrations were significantlly higher in the wt/mut compared to wt/wt group. In heterozygotes, but not in the wt/wt group, serum gastrin and plasma chromogranin A concentrations were significantly higher in patients on long-term treatment compared with those receiving one dose. Also, after long-term treatment serum pepsinogen I concentration was significantly lower in wr/mut compared with wt/wt group of patients. Serum vitamin B12 levels were assessed in 180 patients of different CYP2C19 genotype groups. In 111 patients, receiving one dose of 20 mg omeprazole, no difference in B12 levels were found between heterozygous (wt/mut) and homozygous (wt/wt) groups of patients. However, in 68 patients on long-term therapy, serum vitamin B12 levels were lower in the wt/mut compared to wt/wt. Also, in the wt/mut groups serum vitamin B12 levels were lower in patients on long-term therapy compared with those receiving one dose. In summary, the CYP2C19 polymorphism affects gastric secretory parameters more than H. pylori infection in patients on omeprazole treatment. Further, in patients on long-term treatment the omeprazole effect on the oxyntic mucosa and B12 levels are dependent on CYP2C19 polymorphism.