Структура распределения генетических детерминант эффективности и безопасности нестероидных противовоспалительных препаратов в российской популяции: фокус на CYP2C8, PTGS1 и PTGS2

The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) may be determined by the polymorphic nature of the CYP2C8, PTGS1 and PTGS2 genes.Objective: to analyze the nature of the distribution of CYP2C8*3 (rs10509681), CYP2C8*3 (rs11572080), PTGS1 (rs10306135), PTGS1 (rs12353214) and PTGS2 (rs20417) among residents of the North Caucasus.Patients and methods. The study involved 676 volunteers from Russian, Balkar, Kabardian and Ossetian ethnic groups. Carriage of polymorphic markers CYP2C8, PTGS1 and PTGS2 was determined using real-time polymerase chain reaction.Results and discussion. There were no significant differences between the groups in the rs10509681 and rs11572080 variants of the CYP2C8 gene. In all groups, the carriage of a combination of CYP2C8 and CYP2C9 alleles, encoding the phenotype of normal metabolizers, prevailed with a frequency of about 75% or more. The rs10306135 variant of the PTGS1 gene was found in 5.9% of Russians, 1.1% of Balkars, 5.3% of Kabardians, and 10.6% of Ossetians; variant rs12353214 – in 19.1; 9.4; 10.8 and 9.2%, rs20417 polymorphism of the PTGS2 gene in 0.4; 5; 2.8 and 3.1% respectively.Conclusion. The data obtained can be used to develop a more rational approach to the prescription of NSAIDs, taking into account the genetic characteristics of the local population in ethnic regions.Эффективность и безопасность применения нестероидных противовоспалительных препаратов (НПВП) может определяться полиморфной природой генов CYP2C8, PTGS1 и PTGS2.Цель исследования – анализ характера распределения CYP2C8*3 (rs10509681), CYP2C8*3 (rs11572080), PTGS1 (rs10306135), PTGS1 (rs12353214) и PTGS2 (rs20417) среди жителей Северного Кавказа.Пациенты и методы. В исследовании участвовали 676 добровольцев из русской, балкарской, кабардинской и осетинской этнических групп. Носительство полиморфных маркеров CYP2C8, PTGS1 и PTGS2 определялось с помощью полимеразной цепной реакции в режиме реального времени.Результаты и обсуждение. Значимых различий между группами по вариантам rs10509681 и rs11572080 гена CYP2C8 не получено. Во всех группах преобладало носительство комбинации аллелей CYP2C8 и CYP2C9, кодирующих фенотип нормальных метаболизаторов с частотой около 75% и более. Вариант rs10306135 гена PTGS1 выявлен у 5,9% русских, 1,1% балкарцев, 5,3% кабардинцев и 10,6% осетин; вариант rs12353214 – у 19,1; 9,4; 10,8 и 9,2%, полиморфизм rs20417 гена PTGS2 – у 0,4; 5; 2,8 и 3,1% соответственно.Заключение. Полученные данные могут быть использованы при разработке более рационального подхода к назначению НПВП, учитывающего генетические особенности местного населения в этнических регионах

Features of drug-drug interactions rivaroxaban and calcium channel blockers depending on the ABCB1 genotype (rs1045642 and rs4148738) in patients 80 years of age and older with non-valvular atrial fibrillation

Background. The use of P-glycoprotein (P-gp) inhibitors and carriage of certain ABCB1 polymorphisms can lead to increased concentrations of rivaroxaban and the development of bleeding.The aim of the study. To study the features of drug-drug interactions (DDI) of rivaroxaban in patients over 80 years of age with non-valvular atrial fibrillation depending on the ABCB1 genotype (rs1045642 and rs4148738) using the example of verapamil (P-gp inhibitor) and amlodipine.Materials and methods. One hundred and twenty-eight patients were examined (median age – 87.5 [83–90] years). Genotyping, determination of the minimum equilibrium concentration of rivaroxaban (Cmin, ss), with standardization for the daily dose (Cmin, ss/D), coagulogram and analysis of medical documentation for the presence of clinically relevant non-major bleeding (CRNM) were carried out. Analysis of CRNM was performed depending on the ABCB1 genotype.Results. The use of rivaroxaban with verapamil in comparison with patients not taking calcium channel blockers (CCBs) leads to high Cmin, ss values in the CC genotype (rs1045642, rs4148738); Сmin, ss and Сmin, ss/D in the CT genotype (rs1045642); prothrombin time in the CC genotype (rs1045642), more frequent occurrence of CRNM in the TT  genotype (rs1045642, rs4148738). In  comparison with patients taking amlodipine, it leads to high Cmin, ss values in the CT genotype (rs1045642), a more frequent occurrence of CRNM in the TT genotype (rs1045642, rs4148738). The use of rivaroxaban with amlodipine in comparison with patients not taking CCBs leads to high Cmin, ss and Cmin, ss/D values in the CC genotype (rs1045642) (p < 0.017).Conclusion. The use of verapamil with rivaroxaban in ABCB1 TT carriers (rs4148738 and rs4148738) leads to the development of CRNM in 75 and 78 % of cases, respectively. In  patients taking rivaroxaban, it is advisable to test the ABCB1 genotype (rs4148738 and rs4148738) before adding a P-gp inhibitor to therapy

Study of the Effect of Polymorphic Markers of the NAT2 Gene on the Risk of Adverse Drug Reactions in Patients with Pulmonary Tuberculosis Who Received Isoniazid and Rifampicin

Tuberculosis remains one of the most dangerous and widespread infectious diseases. More than 20 medicinal products are currently available for the treatment of tuberculosis. One of the most serious adverse drug reactions (ADRs) associated with anti-tuberculosis medicines is hepatotoxicity.The aim of the study was to assess the effect of polymorphic markers of the NAT2 gene on the ADR risk in patients with pulmonary tuberculosis who received isoniazid and rifampicin.Materials and methods. The study included 67 patients with different forms of pulmonary tuberculosis who received combination therapy with isoniazid and rifampicin. Single nucleotide polymorphisms (SNPs) of the NAT2 gene were determined by real-time PCR. Statistical processing was performed using SPSS Statistics 20.0.Results: Six SNPs were identified in the NAT2 gene. Based on these SNPs the following phenotypes were determined by the rate of NAT2 acetylation: fast acetylators—6 subjects, intermediate acetylators—24 subjects, and slow acetylators—37 subjects. The study assessed the relationship between the acetylator phenotype and the development of ADRs during combination therapy with isoniazid and rifampicin. Slow acetylators had a significantly greater increase in total bilirubin level (p=0.011) compared to intermediate acetylators. Loss of appetite was more often observed in fast acetylators than in intermediate acetylators (p=0.021).Conclusions. The obtained data suggest interrelation between the slow type of NAT2 acetylation and the risk of ADRs in patients undergoing pulmonary tuberculosis chemotherapy with isoniazid and rifampicin. Out of all the ADRs registered in the study, the fast acetylators were more likely to have loss of appetite, however, the expansion of the study population is needed to verify this observation. The studied polymorphisms have an impact on the development of ADRs in patients undergoing pulmonary tuberculosis chemotherapy with isoniazid and rifampicin and may be used to predict the safety profile of pharmacotherapy in this group of patients

NFLUENCE OF CYP4F2*3 ON RESPONSE TO CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

Background. Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose.Aim. To study the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI).Material and methods. The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9±10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer – the VerifyNow P2Y12 assay.Results. Pharmacogenetic testing showed that 40 (49.4%) of ACS patients had normal genotype (CC), 38 (46.9%) patients were carriers of one associated with reduced drug metabolism allele (CT genotype), and 3 (3.7%) patients were homozygotes for T (TT genotype). Genotype and allele distribution was in the Hardy-Weinberg equilibrium (c2=2.79; p=0.095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU>208) and in patients with a normal response to clopidogrel (PRU<208): 36.8% vs 54.8% (р=0.17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165.34±51.03 PRU vs 174.8±51.06 PRU (p=0.407), respectively, and 29.51±21.59% vs 27.72±18.35%, respectively (p=0.69).Conclusion. Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy

NFLUENCE OF CYP4F2*3 ON RESPONSE TO CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

Background. Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose.Aim. To study the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI).Material and methods. The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9±10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer – the VerifyNow P2Y12 assay.Results. Pharmacogenetic testing showed that 40 (49.4%) of ACS patients had normal genotype (CC), 38 (46.9%) patients were carriers of one associated with reduced drug metabolism allele (CT genotype), and 3 (3.7%) patients were homozygotes for T (TT genotype). Genotype and allele distribution was in the Hardy-Weinberg equilibrium (c2=2.79; p=0.095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU>208) and in patients with a normal response to clopidogrel (PRU<208): 36.8% vs 54.8% (р=0.17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165.34±51.03 PRU vs 174.8±51.06 PRU (p=0.407), respectively, and 29.51±21.59% vs 27.72±18.35%, respectively (p=0.69).Conclusion. Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy

Evaluation of the Influence of <i>CYP2C9* 2, CYP2C9*3</i> Gene Polymorphisms on the Efficacy and Safety of Postoperative Analgesia with Ketoprofen in Patients after Cardiac Surgery

Aim. The aim of the study was to evaluate the efficacy and safety of ketoprofen as an analgesic therapy in patients with CYP2C9*2 (430C&gt;T) rs179985 and CYP2C9*3 (1075A&gt;C) rs1057910 gene polymorphisms after cardiac surgery.Material and methods. The study included 90 patients. Postoperative analgesia was perfomed by ketoprofen 100 mg intramuscularly twice daily. The evaluation of pain was determined daily by Numeric Rating Scale for 5 days after cardiac surgery. The safety of ketoprofen was determined by assessing the severity of gastroenterological symptoms using the Gastrointestinal Symptom Rating Scale questionnaire and determining the frequency of episodes of acute kidney injury. The material for DNA was venous blood. To determine the single nucleotide genetic polymorphisms CYP2C9*2 (430C&gt;T) rs179985 and CYP2C9*3 (1075A&gt;C) rs1057910, the real-time polymerase chain reaction was used.Results. In patients with the AA genotype of CYP2C9*3 polymorphism, the intensity of pain on the numeric rating scale scale (points) was significantly higher than in patients with the AC genotype: 7 [6; 8] vs 6 [5; 6] (р=0,003), 7 [6; 8] vs 6 [5; 6] (р=0,04), 6 [5; 7] vs 5 [4; 5] (р=0,04), 5 [3; 6] vs 3 [3; 4] points (р=0,02) on days 1, 2, 3 and 5 of the postoperative period, respectively. The severity of gastroenterological symptoms was higher in patients with a heterozygous CT genotype for the allelic variant CYP2C9*2 than in patients with a wild CС genotype and amounted to 19 [19; 22] vs 18 [16; 20] points, respectively, (p=0,04). The distribution of genotypes for CYP2C9*2 polymorphisms and CYP2C9*3 polymorphisms between the groups of acute renal injury did not differ significantly.Conclusion. Associations of polymorphisms CYP2C9*3 with a lower intensity of pain syndrome and CYP2C9*2 with a greater severity of gastroenterological symptoms were revealed

Effect of polymorphisms in CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results

Introduction. Apixaban is a direct oral anticoagulant prescribed for treatment and prevention of venous thromboembolism (VTE) and for prevention of stroke in patients with nonvalvular atrial fibrillation. Direct oral anticoagulants (DOACs) such as apixaban are rapidly replacing warfarin therapy due to improved efficacy and safety profile shown in clinical trials. However, anticoagulants can cause serious and adverse drug reactions (ADRs).Aim. Study of the effect of carriage of polymorphisms in CYP3A4*22 (rs35599367) C&gt;T, CYP3A5*3 (rs776746) A&gt;G, ABCB1 (rs4148738) C&gt;T and ABCB1 (rs1045642) C&gt;T genes on the change in prothrombin time (PT) and activated partial thromboplastin time (aPTT) in patients using apixaban.Materials and methods. A total of 36 patients were enrolled onto this prospective observational study. All patients received apixaban at doses in accordance with instructions on how to administer the drug. Atrial fibrillation was diagnosed in 26 patients, and secondary thrombotic complications in 23 patients. To perform pharmacogenetic tests and measure aPTT and PT parameters, venous blood samples from each patient were drawn on Days 4-5 after prescription of apixaban. The PharmGKB database was used to select candidate genes for the study. Genotyping was performed using the real-time polymerase chain reaction technique. Statistical analysis: data were analyzed by using IBM SPSS Statistics program, Version 23.0.Results. In our study, we assessed the effect of polymorphisms in ABCB1 (rs1045738) C&gt;T, ABCB1 (rs4148642) C&gt;T genes on the aPTT and PT parameters. No statistically significant associations were found.Conclusion. The differences between PT and APTT values in patients using apixaban in the groups with different polymorphisms in ABCB1 (rs1045738) C&gt;T, ABCB1 (rs4148642) C&gt;T gene were not statistically significant. Further studies are necessary to assess the effect of pharmacogenetics on the safety and efficacy profile of apixaban