CYP2C9 gene polymorphisms influence on antihypertensive effectiveness and hypouricemic effect of losartan among patients with arterial hypertension: an observational study.

OBJECTIVES: CYP2C9 gene polymorphic variants can decrease the effects of losartan, reducing active metabolite (E-3174) formation. Study aims to determine the influence of *2 (+430C>T; rs799853) and *3 (+1075A>C; rs1057910) CYP2C9 gene polymorphic variants on the hypotensive and uricosuric effect of losartan on patients with arterial hypertension. METHODS: Eighty one patients with stage 1-2 arterial hypertension newly diagnosed with ABMP were enrolled in the study. Physicians started losartan treatment and then we measured urine concentration of E-3174/losartan to estimate CYP2C9 activity. After 3-month losartan treatment we compared effectiveness of the therapy with ABPM and plasma uric acid level between carriers of CYP2C9 *1/*1 and CYP2C9 gene polymorphic variants (*2 and *3). RESULTS: Carriage of CYP2C9*2 and CYP2C9*3 alleles reduced the hypotensive effect of losartan (p<0.001, OR=8.13 (95% CI, 2.75-23.97)). Analysis of the ABPM data revealed that blood pressure was significantly higher in patients with polymorphic genotypes. There was no significant difference in uric acid level in plasma and losartan and its metabolite concentration in urine between genotypes. CONCLUSIONS: Carriage of low function polymorphic variants of the CYP2C9 gene (*2 and *3) reduced the hypotensive effect of losartan according to ABPM and don't affect uric acid level in plasma and E-3174/losartan in urine.

Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma.

OBJECTIVES: Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). METHODS: 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). RESULTS: The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). CONCLUSIONS: CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Effect of CYP2C9, PTGS-1 and PTGS-2 gene polymorphisms on the efficiency and safety of postoperative analgesia with ketoprofen.

OBJECTIVES: Patients undergoing cardiac surgery develop post-sternotomy pain syndrome. The aim of this study was evaluation of the influence of CYP2C9, PTGS-1 and PTGS-2 genes polymorphisms on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. METHODS: The study included 90 patients undergoing cardiac surgery. A real-time polymerase chain reaction was used for the detection of single nucleotide polymorphisms (SNP). Pain intensity was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury (AKI) was determined by Kidney Disease Improving Global Outcomes criteria. RESULTS: Pain intensity by the NRS score was significantly higher in patients with CYP2C9*3 АA genotype compared to АC genotype: 7 [1,10] and 6 [2,7] (p=0.003); 7 [1,10] and 6 [2,7] (p=0.04); 6 [0; 10] and 5 [2,6] (p=0.04); 5 [0; 8] and 3 [0; 8] (p=0.02), on days 1, 2, 3 and 5 in the postoperative period, respectively. GSRS score was higher in patients with CYP2C9*2 CT genotype compared to CС genotype: 19 [15; 42] and 18 [15,36] (p=0.04), respectively. There were no significant differences in the pain intensity, dyspepsia severity and AKI frequency in patients with homozygous and heterozygous genotypes for PTGS-1 rs10306135, PTGS-1 rs12353214, PTGS-2 rs20417. CONCLUSIONS: CYP2C9*3 and CYP2C9*2 gene polymorphisms may affect efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Antihypertensive Effect Of Amlodipine In Co-Administration With Omeprazole In Patients With Hypertension And Acid-Related Disorders: Cytochrome P450-Associated Aspects.

BACKGROUND: CYP2C19 and CYP3A are the main enzymes involved in omeprazole metabolism, while CYP3A is the principal enzyme family for amlodipine biotransformation. Concomitant use of these drugs in patients with hypertension and acid-related disorders (ARD) might lead to drug-drug interaction. PURPOSE: The aim of the study was to find if adding omeprazole for treating ARD to amlodipine long-term therapy of hypertension influenced blood pressure of CYP2C19 polymorphism carriers. PATIENTS AND METHODS: Fifty-one patients diagnosed with hypertension and ARD were enrolled in the study. Evaluation of antihypertensive therapy was performed by office (OBPM) and ambulatory (ABPM) blood pressure monitoring. Peripheral venous blood was collected for DNA extraction and real-time polymerase chain reaction was performed for CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C-806T (rs12248560) polymorphisms analysis. RESULTS: Of 51 patients there were 21 extensive metabolizers (EMs), 18 ultrarapid metabolizers (UMs) and 12 intermediate metabolizers (IMs). The results of OBPM showed that antihypertensive effect was significantly more pronounced in IMs compared to EMs or UMs and the average group value in the following parameters: average office systolic blood pressure (BP), dynamics of the average office systolic BP. According to dynamics of diastolic BP, the antihypertensive effect was also significantly higher in IMs than in UMs and the average group value. The results of ABPM revealed that there was a significantly more pronounced antihypertensive effect in IMs compared to all other analyzed groups according to the dynamics of both daytime systolic and 24 hr diastolic BP. The average daytime diastolic BP and its dynamics, the average 24 hr systolic BP and its dynamics were higher in IMs compared to EMs and UMs. CONCLUSION: Adding omeprazole to long-term amlodipine therapy in patients with hypertension and ARD may lead to a significantly more pronounced antihypertensive effect in patients genotyped CYP2C19 IMs.

CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole.

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 6ß-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 6ß-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.

Do CYP2C19 and ABCB1 gene polymorphisms and low CYP3A4 isoenzyme activity have an impact on stent implantation complications in acute coronary syndrome patients?

AIM: The aim of this study was to determine the impact of CYP2C19 and ABCB1 gene polymorphisms and CYP3A4 isoenzyme activity on stent implantation complications among patients with an acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). PATIENTS AND METHODS: Seventy-six patients (median age 63, range 37-91 years) with an ACS who underwent PCI were screened for CYP2C19 and ABCB1 gene polymorphisms with real-time polymerase chain reaction: CYP2C19*2, CYP2C19*17, and ABCB1 3435. CYP3A4 isoenzyme activity was determined by urine cortisol and 6-beta-hydroxycortisol levels. Stent implantation complications such as stent thrombosis (n=2) and restenosis (n=1) were observed among drug-eluting stent recipients. RESULTS: Low mean 6-beta-hydroxycortisol/cortisol ratio is indicative of impaired CYP3A4 activity and was associated with higher risk of thrombosis (b coefficient=0.022, SE 0.009, p=0.021 in the linear regression model). The increase in the length of the implanted stent was associated with higher risk of restenosis (b coefficient=0.006, SE=0.002, p=0.001 in the linear regression model). The presence of the CYP2C19*2 polymorphism did not affect the incidence of stent thrombosis (b coefficient=-1.626, SE=1.449, p=0.262 in the logistic regression model), nor did the CYP2C19*17 (b coefficient=-0.907, SE=1.438, p=0.528 in the logistic regression model) and ABCB1 3435 polymorphisms (b coefficient=1.270, SE=1.442, p=0.378 in the logistic regression model). CONCLUSION: We did not find evidence that the presence of CYP2C19*2, CYP2C19*17, and ABCB1 3435 polymorphisms may jeopardize the safety of stent implantation in patients with an ACS. Patients with low CYP3A4 isoenzyme activity may have increased risk of stent thrombosis.

Genetic Polymorphisms of Cytochrome P450 Enzymes and Transport Proteins in a Russian Population and Three Ethnic Groups of Dagestan.

AIM: The objective of this study was to investigate the prevalence of polymorphic markers of the CYP2C19, CYP2C9, CYP2D6, SLCO1B1, and ABCB1 genes among the three ethnic groups in Dagestan and compare it with the carrier frequency of these markers among the Russian population living in Moscow. METHODS: The study involved 186 healthy, unrelated, and chronic medication-free volunteers (53 males and 133 females) of the three ethnic groups in the Dagestan Republic: 46 Laks, 90 Avars, and 50 Dargins. Genotyping was performed using real-time polymerase chain reaction-based methods. The allelic prevalences of the three Dagestan peoples were compared with ethnic Russians from the Moscow region. RESULTS: Statistically significant differences for the following gene polymorphisms: CYP2C19*17, CYP2C9*3, ABCB1 (C3435T), SLCO1B1*5 were found between the Russian population and the three ethnic groups of the Dagestan republic. CONCLUSION: The data obtained from this study will help with prioritization genotyping in the region.

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

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.