CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole
Authors Denisenko NP, Sychev DA, Sizova ZM, Smirnov VV, Ryzhikova KA, Sozaeva ZA, Grishina EA
Received 13 December 2017
Accepted for publication 17 March 2018
Published 18 June 2018 Volume 2018:11 Pages 107—112
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Andrew Yee
Peer reviewer comments 2
Editor who approved publication: Dr Martin Bluth
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: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation.
Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole.
Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy.
Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal–Wallis test (p=0.014).
Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs.
Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor
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