Urine metabolic ratio of omeprazole in relation to CYP2C19 polymorphisms in Russian peptic ulcer patients

Natalia P Denisenko,1–3 Dmitriy A Sychev,2 Zhanna M Sizova,3 Valeriy V Smirnov,4,5 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Elena A Grishina1 1Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 3Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 5Laboratory of Clinical Pharmacology, National Research Centre, Institute of Immunology, Federal Medical Biological Agency, Moscow, Russia Background: CYP2C19 is known to be the main enzyme of biotransformation of proton pump inhibitors (PPIs), whereas the CYP2C19 gene is highly polymorphic. Genotyping and phenotyping together represent more reliable data about patient’s CYP2C19 activity.Purpose: The aim of the study was to investigate the applicability of urine metabolic ratio of omeprazole for CYP2C19 phenotyping in Russian peptic ulcer patients with different CYP2C19 genotypes.Patients and methods: A total of 59 patients (19 men and 40 women) aged 18–91 years (mean age 53.5±15.1 years) from four Moscow clinics who were diagnosed with an endoscopically and histologically proven peptic ulcer or had a history of endoscopically and histologically proven ulcers in the past were recruited. Peripheral venous blood (6 mL) was collected for DNA extraction, and real-time polymerase chain reaction was performed for the analysis of CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C-806T (rs12248560) polymorphisms. Urine samples of patients were collected in the morning between 6 am and 9 am, before food or drug intake, after at least 3 days of twice daily (b.i.d.) omeprazole intake. Omeprazole and 5-hydroxyomeprazole concentrations in the urine were measured using high-performance liquid chromatography with mass spectrometry.Results: Of the 59 patients, there were 27 (45.8%) extensive metabolizers (EMs; CYP2C19*1/*1), 16 (27.1%) ultrarapid metabolizers (UMs; CYP2C19*1/*17, CYP2C19*17/*17), 14 (23.7%) intermediate metabolizers (IMs; CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*3/*17) and two (3.4%) poor metabolizers (PMs; CYP2C19*2/*2). Median metabolic ratio (25%–75% percentiles) were 1.03 (0.69–1.36) for EMs, 1.95 (1.33–2.68) for UMs, 1.40 (0.78–2.13) for IMs+PMs and 1.26 (0.82–1.99) for the whole sample. A statistically significant difference in metabolic ratio (Mann–Whitney U test) was found between UMs and EMs (p=0.001) and in the multiple comparison Kruskal–Wallis test (p=0.005).Conclusion: We found a connection between particular CYP2C19 genotypes and urine metabolic ratio of omeprazole in Russian peptic ulcer patients. This method needs to be improved as in our modification it worked mainly for UMs and did not differentiate all patients according to omeprazole biotransformation activity. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor