Optimal Dose of Omeprazole for CYP2C19 Extensive Metabolizers in Anti-Helicobacter pylori Therapy: Pharmacokinetic Considerations.

Abstract

Proton pump inhibitors are occasionally used in therapy for eradicating Helicobacter pylori in the combination with antimicrobials, [1][2][3][4][5] for the prevention of gastric and duodenal ulcer diseases.1,2) Triple therapy using omeprazole, amoxicillin, and clarithromycin is now recommended for anti-H. pylori therapy because of its high eradication rate (greater than 90%), [3][4][5] although problems with this therapy have arisen including the resistance of H. pylori to clarithromycin by failure. 2,3)Omeprazole is extensively metabolized into the primary metabolites of 5Ј-hydroxyomeprazole and omeprazole sulfone (Fig. 1). Formation of the 5Ј-hydroxyomeprazole is mediated mainly by cytochrome P450 2C19 (CYP2C19) with only a minor contribution of CYP3A4 and others. 6) CYP2C19, often referred to as S-mephenytoin 4Ј-hydroxylase, shows genetically determined polymorphism of enzyme activity with bimodal distributions. 7) In 1994, two mutant alleles, CYP2C19*2 and CYP2C19*3, were found in addition to a wild-type allele, CYP2C19*1, and six different genotypic patterns were theoretically defined. [8][9][10] In our previous studies, the pharmacokinetics of omeprazole and gastric pH after omeprazole administration in healthy subjects were also defined by bimodal distribution, and two groups were genetically assigned based on CYP2C19 genotypes: extensive metabolizers and poor metabolizers. 11,12) In anti-H. pylori therapy using omeprazole (20 mgϫ2/d for 1 week), amoxicillin (500 mgϫ4/d for 1 week), and clarithromycin (200 mgϫ4/d for 1 week), patients who were poor metabolizers all achieved eradication, while 17% of extensive metabolizers failed. 13,14) Several studies have shown that this therapeutic inefficacy might be overcome by high-dose omeprazole.1) Recently, Furuta et al. 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.In the present study, a single oral dose of omeprazole 20, 40, and 80 mg was administered to 7 healthy Japanese subjects with the CYP2C19 genotype. The recommended dose of omeprazole for extensive metabolizers was estimated in anti-H. pylori therapy based on pharmacokinetic considerations. MATERIALS AND METHODS ChemicalsOmeprazole and its two metabolites, 5Ј-hydroxyomeprazole and omeprazole sulfone, were obtained In anti-Helicobacter pylori therapy using omeprazole and antimicrobials, the efficacy can be related to the CYP2C19 genotype groups; the eradication rates were 83% in extensive metabolizers and 100% in poor metabolizers. The present study was undertaken to help predict the optimal dosage of omeprazole for extensive metabolizers in this therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n‫)4؍‬ and poor metabolizers (n‫,)3؍‬ participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for...

New concepts of resistance in the treatment of Helicobacter pylori infections

“…Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest among the three groups. Eradication rates with triple therapy are inversely related to the ability to metabolize the PPIs (ie the RM group has lower eradication rate compared to other groups) 30,[33][34][35][36][37][38] .…”

“…Studies are needed in Western populations to confirm the success seen in Japan and to identify the dose and doing intervals of each PPI to ensure the best effect. Clinical trials have suggested that approximately 80 mg of omeprazole given every 12 hours was sufficient 36 . Clinical studies with every 6 hour dosing have proven successful in Japan 51,68 .…”

Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals

“…The clinical consequences of the CYP2C19 gene polymorphisms have not been fully understand but can be illustrated with the case of proton-pump inhibitors. The EMs metabolizes these drugs at a speed that requires doses up to four times greater than PMs to reach similar serum concentrations and effects [12,13]. …”

Different Contribution of CYP2C19 in the in Vitro Metabolism of Three Proton Pump Inhibitors.

“…A series of clinical studies on the CYP2C19 genotype and the pharmacokinetics and pharmacodynamics of three proton pump inhibitors (PPIs), omeprazole, lansoprazole and rabeprazole, were conducted to establish the individualized pharmacotherapy based on the CYP2C19 genotyping. [1][2][3][4][5] The subjects were classified into homo extensive metabolizers, hetero extensive metabolizers and poor metabolizers according to the CYP2C19 genotype diagnosed. The findings were summarized as follows: 1) plasma concentrations of omeprazole and lansoprazole after single oral administration were defined by the CYP2C19 genotype, whereas rabeprazole was not, 2) the CYP2C19 genotype-dependency of lansoprazole was weaker than omeprazole, and 3) hetero extensive metabolizers could be included with homo extensive metabolizers to be extensive metabolizers.…”