Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Abstract

Proton pump inhibitors, such as omeprazole (OPZ), lansoprazole and rabeprazole (RPZ), have been widely used as acid inhibitory agents for the treatment of upper gastrointestinal diseases. 1 OPZ is a substituted benzimidazole, which effectively inhibits gastric acid secretion by irreversibly binding to the proton pump (H + ,K + -ATPase) in gastric parietal cells, 2, 3 and is mainly metabolized by a genetically determined enzyme, S-mephenytoin-4¢-hydroxylase (CYP2C19), in the liver to hydroxyomeprazole (OH-OPZ). 4±8 OPZ is partially metabolized by CYP3A4 to omeprazole sulphone (OPZ-SFN), which is then metabolized to hydroxyomeprazole sulphone (OH-OPZ-SFN) by CYP2C19. 9 In individuals with a poor metabolizer (PM) phenotype or genotype of CYP2C19, the SUMMARY Background: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. Aim: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. Methods: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On postdose days 1 and 8, 24-h pro®les of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined.

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2‐receptor antagonist

“…36 The contribution of the CYP2C19-related polymorphism to the metabolism of the four main proton-pump inhibitors varies, but omeprazole is the most affected. 36 In previous reports, the relative ratios of the mean area under the curve (AUC) have been significantly different among the three genotype groups after a single administration of omeprazole 20 mg (homo-EMs : heteroEMs : PMs ¼ 38 ). In our study, the median intragastric 24-h pH values after a 7-day regimen of omeprazole 20 mg were 3.7 in the homo-EMs, 4.4 in the heteroEMs, and 6.3 in the PMs, which are similar to the results of the previous report.…”

“…In our study, the median intragastric 24-h pH values after a 7-day regimen of omeprazole 20 mg were 3.7 in the homo-EMs, 4.4 in the heteroEMs, and 6.3 in the PMs, which are similar to the results of the previous report. 38 Although it was supposed that there would be considerable differences after repeated administration of omeprazole 10 mg, previous reports have not mentioned them. In our study, with omeprazole 10 mg, the intragastric pH increased and the median pH value and pH > 4HT increased in the daytime, depending on the CYP2C19 genotype status, but at night the intragastric pH did not increase and these parameters did not significantly increase in the homoand hetero-EMs.…”

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…(Table 3). In contrast, the NM metabolizer phenotype was shown to have lower plasma levels of PPI, which correlated with reduced acid suppression [40,41]. …”

“…Similarly, the AUC following the administration of equal doses of pantoprazole in PM was sixfold higher than NM and IM [43,44]. Although reports have documented the impact of CYP2C19 genotype on PK for both rabeprazole [40,45–49] and esomeprazole [50,51], these associations with PK parameters such as AUC were of smaller magnitude than the effects reported for other PPIs, suggesting less influence of CYP2C19 genotype on these newer generations PPIs. This is not surprising given that rabepeprazole and esomeprazole are less dependent on CYP2C19 for their metabolism (Table 1).…”

“…Additionally, while the CYP2C19 - inferred metabolic phenotype was consistently associated with acid suppression and therapeutic outcomes for PPIs with extensive CYP2C19 metabolism, it is not always the case with esomeprazole and rabeprazole. While some studies have documented genotype dependent differences in acid suppression and outcomes, others showed no relation between genotype and degree of acid suppression or outcomes for rabeprazole and esomeprazole [40,48,53,71,73,108]. This may be attributed in part to their lesser dependence on CYP2C19 metabolism, the higher potency of these PPIs [53,109,110], compared to other PPIs, lack of *17 testing [71], or combination of these factors, leading to diminished differences between the different CYP2C19 metabolizer phenotypes.…”