Denisenko Natalia P, Sychev Dmitriy A, Sizova Zhanna M, Smirnov Valeriy V, Ryzhikova Kristina A, Sozaeva Zhannet A, Grishina Elena A
Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia.
Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia.
Pharmgenomics Pers Med. 2017 Sep 27;10:253-259. doi: 10.2147/PGPM.S141935. eCollection 2017.
CYP2C19 is known to be the main enzyme of biotransformation of proton pump inhibitors (PPIs), whereas the gene is highly polymorphic. Genotyping and phenotyping together represent more reliable data about patient's CYP2C19 activity.
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 genotypes.
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 (rs4244285), (rs4986893) and (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.
Of the 59 patients, there were 27 (45.8%) extensive metabolizers (EMs; CYP2C19*1/1), 16 (27.1%) ultrarapid metabolizers (UMs; CYP2C191/17, CYP2C1917/17), 14 (23.7%) intermediate metabolizers (IMs; CYP2C191/2, CYP2C192/17, CYP2C193/17) and two (3.4%) poor metabolizers (PMs; CYP2C192/*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 test) was found between UMs and EMs (=0.001) and in the multiple comparison Kruskal-Wallis test (=0.005).
We found a connection between particular 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.
已知CYP2C19是质子泵抑制剂（PPIs）生物转化的主要酶，而该基因具有高度多态性。基因分型和表型分型共同提供了关于患者CYP2C19活性的更可靠数据。
本研究旨在探讨奥美拉唑尿代谢率在俄罗斯不同基因型消化性溃疡患者中用于CYP2C19表型分型的适用性。
从莫斯科的四家诊所招募了59例年龄在18 - 91岁（平均年龄53.5±15.1岁）的患者（19名男性和40名女性），这些患者经内镜和组织学证实患有消化性溃疡或既往有内镜和组织学证实的溃疡病史。采集外周静脉血（6 mL）用于DNA提取，并进行实时聚合酶链反应以分析(rs4244285)、(rs4986893)和(rs12248560)多态性。患者的尿液样本在早上6点至9点之间收集，在进食或服药前，且在每日两次（bid）服用奥美拉唑至少3天后。使用高效液相色谱 - 质谱法测量尿液中奥美拉唑和5 - 羟基奥美拉唑的浓度。
59例患者中，有27例（45.8%）为广泛代谢者（EMs；CYP2C19*1/1），16例（27.1%）为超快代谢者（UMs；CYP2C191/17，CYP2C1917/17），14例（23.7%）为中间代谢者（IMs；CYP2C191/2，CYP2C192/17，CYP2C193/17），2例（3.4%）为慢代谢者（PMs；CYP2C192/*2）。EMs的中位代谢率（25% - 75%百分位数）为1.03（0.69 - 1.36），UMs为1.95（1.33 - 2.68），IMs + PMs为1.40（0.78 - 2.13），整个样本为1.26（0.82 - 1.99）。在UMs和EMs之间发现代谢率存在统计学显著差异（Mann - Whitney检验，P = 0.001），在多重比较的Kruskal - Wallis检验中也存在差异（P = 0.005）。
我们发现俄罗斯消化性溃疡患者中特定的CYP2C19基因型与奥美拉唑尿代谢率之间存在关联。该方法需要改进，因为在我们的改进中它主要适用于UMs，并且不能根据奥美拉唑生物转化活性区分所有患者。
