Rapid and ultra-rapid metabolizers with CYP2C19 *17 polymorphism do not respond to standard therapy with proton pump inhibitors

Abstract

Introduction and objectivePolymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects.MethodsDNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH.ResultsOf the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers.ConclusionOur study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.

Farmacogenômica e Doença Cardiovascular: Onde Estamos e Para Onde Vamos

“…Os portadores da variante CYP2C19*17 foram denominados metabolizadores ultrarrápidos. 83 A raça parece ser outro fator com papel importante nesse cenário. Cresci et al 84 compararam o efeito do polimorfismo do CYP2C19 sobre eventos CVs adversos entre pacientes com infarto agudo do miocárdio em caucasianos e afroamericanos tratados com clopidogrel.…”

Role of Acid Suppression in Acid-related Diseases: Proton Pump Inhibitor and Potassium-competitive Acid Blocker

“…9 The distribution of CYP2C19 phenotypes was divided into 4 phenotypes: extensive metabolizers (EM), intermediate metabolizers, ultra-rapid metabolizers, and poor metabolizers. 10 CYP2C19 is responsible for > 80% of the metabolism of omeprazole, lansoprazole, and pantoprazole metabolism. 11 Esomeprazole, the S-isomer of omeprazole, is metabolized to a less extent by CYP2C19 than omeprazole.…”

Personalized therapy for Helicobacter pylori: CYP2C19 genotype effect on first‐line triple therapy

“…While heterozygote individuals with one normal activity allele and one variant allele associated with increased activity (*17), CYP2C19 *1/*17 are considered extensive metabolizers (EM) although this continues to be under study . Clinical implication of CYP2C19 *17/*17 polymorphism relies on the following: If PPIs are quickly metabolized, standard PPIs dose fails to adequately suppress acid secretion, and H pylori eradication therapy will be less effective if the microorganism is sensitive to antibiotics . A recent work in Colombia to eradicate H pylori , using triple therapy with clarithromycin or levofloxacin combined with amoxicillin, reported that although the organism was sensitive to these antibiotics, there was variability with achieved eradication .…”

“…21,23 Clinical implication of CYP2C19*17/*17 polymorphism relies on the following: If PPIs are quickly metabolized, standard PPIs dose fails to adequately suppress acid secretion, and H pylori eradication therapy will be less effective if the microorganism is sensitive to antibiotics. 19,21,24,25 A recent work in Colombia to eradicate H pylori, using triple therapy with clarithromycin or levofloxacin combined with amoxicillin, reported that although the organism was sensitive to these antibiotics, there was variability with achieved eradication. 26 These results may suggest the possibility that additional factors, different from antimicrobial resistance, can influence treatment effectiveness in our population.…”