Pharmacogenetics of proton pump inhibitors and prevalence of the CYP2C19*2 and *17 variants in the Central European population

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F22%3A00127205" target="_blank" >RIV/00216224:14310/22:00127205 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Pharmacogenetics of proton pump inhibitors and prevalence of the CYP2C19*2 and *17 variants in the Central European population

Popis výsledku v původním jazyce

Objective: Proton pump inhibitors (PPIs) are administered to patients with acid peptic disorders, such as gastroesophageal reflux disease. The efficiency of treatment by most PPIs largely depends on the cytochrome P450 2C19 (CYP2C19). The activity of this enzyme, genetically determined by the CYP2C19*2 (rs4244285) and CYP2C19*17 (rs12248560) allele variants, can be used to predict the efficacy of this enzyme and, thus, the rate of PPI metabolization. Nevertheless, the phenotype of a novel group of „ambivalent“ metabolizers with both the CYP2C19*2 and CYP2C19*17 variants is unknown. This work aims to evaluate the distribution of metabolizers, mainly focusing on the „ambivalent“ metabolizers in the Central European population and to determine their CYP2C19 metabolic activity. Methods: 545 patients were included in our study; of these, 58 used lansoprazole (Lanzul, 30 mg). Blood samples were drawn to 9 ml K3EDTA and genomic DNA was isolated. Genotypes of two variants CYP2C19*2 and *17 were determined using qPCR and haplogenotypes were evaluated. In patients using lansoprazole, blood samples were taken 3 hours after oral administration of the drug, plasma was transferred into 1.5 ml tubes immediately and stored at -80°C. A therapeutic drug monitoring approach was used to determine the patient‘s phenotype. Plasma concentrations of lansoprazole and its metabolite 5-hydroxylansoprazole were measured by liquid chromatography with absorbance or mass spectrometry detection. Results: Minor allele frequencies in the studied population were 14.7% for the CYP2C19*2 and 25.7% for the CYP2C19*17 variants. Individuals without any variant allele, known as extensive metabolizers (*1*1/*1*1; 36.2%), were the most common. Ultrarapid and rapid metabolizers (*1*17/*1*1 and *17*17/*1*1) were represented by 36.0%. Intermediate metabolizers were less common (*1*1/*1*2; 18.2%) and only 1.5% of participants were poor metabolizers (*1*1/*2*2). 8.3% of participants were shown to be „ambivalent“ metabolizers (*1*17/*1*2), a group whose phenotype was not known. Based on the metabolization rate, the phenotype of ambivalent metabolizers resembled that of extensive metabolizers evaluated in this study. There was no association between concentration of lansoprazole/5-hydroxylansoprazole and metabolic ratio/sex/smoking/alcohol consumption (p &gt; 0.05). Conclusions: This study revealed that ambivalent metabolizers are relatively common in the Central European population and should be considered when discussing the rate of metabolization of PPIs. Their phenotype seems to be close to that of extensive metabolizers, which can play an important role in personalized pharmacotherapy by PPIs in these patients.

Název v anglickém jazyce

Pharmacogenetics of proton pump inhibitors and prevalence of the CYP2C19*2 and *17 variants in the Central European population

Popis výsledku anglicky

Objective: Proton pump inhibitors (PPIs) are administered to patients with acid peptic disorders, such as gastroesophageal reflux disease. The efficiency of treatment by most PPIs largely depends on the cytochrome P450 2C19 (CYP2C19). The activity of this enzyme, genetically determined by the CYP2C19*2 (rs4244285) and CYP2C19*17 (rs12248560) allele variants, can be used to predict the efficacy of this enzyme and, thus, the rate of PPI metabolization. Nevertheless, the phenotype of a novel group of „ambivalent“ metabolizers with both the CYP2C19*2 and CYP2C19*17 variants is unknown. This work aims to evaluate the distribution of metabolizers, mainly focusing on the „ambivalent“ metabolizers in the Central European population and to determine their CYP2C19 metabolic activity. Methods: 545 patients were included in our study; of these, 58 used lansoprazole (Lanzul, 30 mg). Blood samples were drawn to 9 ml K3EDTA and genomic DNA was isolated. Genotypes of two variants CYP2C19*2 and *17 were determined using qPCR and haplogenotypes were evaluated. In patients using lansoprazole, blood samples were taken 3 hours after oral administration of the drug, plasma was transferred into 1.5 ml tubes immediately and stored at -80°C. A therapeutic drug monitoring approach was used to determine the patient‘s phenotype. Plasma concentrations of lansoprazole and its metabolite 5-hydroxylansoprazole were measured by liquid chromatography with absorbance or mass spectrometry detection. Results: Minor allele frequencies in the studied population were 14.7% for the CYP2C19*2 and 25.7% for the CYP2C19*17 variants. Individuals without any variant allele, known as extensive metabolizers (*1*1/*1*1; 36.2%), were the most common. Ultrarapid and rapid metabolizers (*1*17/*1*1 and *17*17/*1*1) were represented by 36.0%. Intermediate metabolizers were less common (*1*1/*1*2; 18.2%) and only 1.5% of participants were poor metabolizers (*1*1/*2*2). 8.3% of participants were shown to be „ambivalent“ metabolizers (*1*17/*1*2), a group whose phenotype was not known. Based on the metabolization rate, the phenotype of ambivalent metabolizers resembled that of extensive metabolizers evaluated in this study. There was no association between concentration of lansoprazole/5-hydroxylansoprazole and metabolic ratio/sex/smoking/alcohol consumption (p &gt; 0.05). Conclusions: This study revealed that ambivalent metabolizers are relatively common in the Central European population and should be considered when discussing the rate of metabolization of PPIs. Their phenotype seems to be close to that of extensive metabolizers, which can play an important role in personalized pharmacotherapy by PPIs in these patients.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů