CYP2D6 Polymorphisms Research Articles

CYP1A1 and CYP2D6 Polymorphisms and Susceptibility to Chronic Myelocytic Leukaemia.

CYP1A1 and CYP2D6 are both xenobiotic metabolizing enzymes belonging to the CYP450 enzyme family. Polymorphisms in these genes vary between individuals, resulting in dissimilar patterns of susceptibility to the effects of carcinogenic substances and drugs. In a prospective study, the influence of CYP1A1*2C and CYP2D6*4 gene polymorphisms on the susceptibility to chronic myelocytic leukaemia (CML) were investigated. Prevalence of CYP1A1*2C and CYP2D6*4 was detected in blood specimens from three hundred participants - two hundred patients and a hundred healthy individuals as a control group, using PCR-RFLP. CYP1A1 Ile/Val and Val/Val genotype frequency in our study population was 82% & 15% in CML patients and 55% & 8% in controls, respectively. This suggests that carriers had an elevated risk (OR=18.38, 95% CI=7.364-45.913, p value; =0.000 and OR=23.125,95 % CI=7.228-73.980, p value=0.000, respectively). Individuals carrying the CYP2D6 heterozygous genotype (IM) were notably fewer in number within the CML group at 43.5%, as opposed to 93% of the controls. This suggests that the IM genotype may have a prophylactic function in lowering CML risk (OR=0.036, 95% CI=0.005-0.271, p value =0.001). In spite of the distribution of the homozygous mutant (PM) genotype being higher in cases with CML (87% as opposed to 6% in the control), this difference was deemed non-significant (OR=0.558, 95% CI=0.064-4.845, p value =0.597). These findings indicate that polymorphic CYP1A1 and CYP2D6 genes affect the susceptibility to CML.

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects.

Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP)enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters. A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. Volunteers (n = 26; aged 24 ± 3years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24h, 436 ± 140ng/mL and at 72h, 40 ± 26ng/mL; AUC0-72 32,868 ± 10,713ng/mL⋅h; and Cmax 2074 ± 604ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24h (23%, 391ng/dL vs 511ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6h vs 14.1h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.

Influence of CYP2D6*5 and *10 polymorphism on the pharmacokinetics of nebivolol in healthy Chinese subjects.

Nebivolol, a selective β1 adrenoreceptor antagonist, is predominantly metabolized by cytochrome P450 (CYP)2D6 and shows a wide interindividual variability in pharmacokinetics. The present study was conducted to evaluate the effects of the major CYP2D6 polymorphisms on nebivolol disposition in healthy Chinese volunteers. Twenty-eight volunteers were enrolled and classified as CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10 and CYP2D6*5 carriers according to their genotypes. The concentration of nebivolol was determined by high-performance liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters and genotypes was evaluated using the unpaired t test or analysis of variance. We evaluated the effects of CYP2D6*5 and *10 polymorphism on the pharmacokinetics of nebivolol. Plasma nebivolol peak concentration and area under the curve (AUC(0-48h) and AUC(0-∞) ) were significantly higher in subjects with CYP2D6*5 and CYP2D6*10/*10 polymorphism than those in subjects with wild-type CYP2D6 (CYP2D6*1/*1), whereas its plasma clearance was significantly lower in the CYP2D6*10/*10 and CYP2D6*5 carriers. No significant differences in the peak time and terminal half-life of nebivolol were observed among CYP2D6*10/*10, CYP2D6*1/*1 and CYP2D6*5 carriers. Both CYP2D6*5 and *10 polymorphism altered the pharmacokinetics of nebivolol in healthy Chinese volunteers. Further studies are required to investigate the effects of these single-nucleotide polymorphisms on the pharmacokinetics, pharmacodynamics and toxicity of nebivolol.

Genetic Polymorphisms of CYP2D6: Prevalence in Healthy Kurds

Background: Identifying the genetic polymorphisms of drug metabolizing enzyme CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence of the CYP2D6 polymorphisms among Kurds is scarce. Objective: In this study, we explored the CYP2D6 polymorphisms among Kurds. Methods: Four hundred and fifty-nine unrelated healthy Kurds were recruited for the study. DNA was extracted from whole blood and was then used for genotyping CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific multiplex Polymerase Chain Reaction (PCR). Conclusion: The data add to our knowledge of CYP2D6 alleles, the genotypes and the distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles confer no function and gene duplication. CYP2D6 polymorphisms were found to be very heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation of drug therapy adjustment based on CYP2D6 genotype may help to understand the clinical consequences of CYP2D6 polymorphisms.

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial.

AimsPupillography is a noninvasive and cost‐effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP‐binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics.MethodsTwenty‐four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro‐aripiprazole and olanzapine plasma concentrations were measured by high‐performance liquid chromatography–tandem mass spectrometry.ResultsAripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes.ConclusionsIn conclusion, aripiprazole and its main metabolite, dehydro‐aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

Pharmacogenetics of the safety of phenazepam in alcohol withdrawal syndrome: haplotype and combinatorial analyses of polymorphic variants in the pharmacokinetic factor genes

Phenazepam is a benzodiazepine tranquilizer that is widely used in Russia. The drug is metabolized by cytochrome P450 3A (CYP3A) isozymes. Since their substrates have an affinity for P-glycoprotein, the polymorphic variants in the ABCB1 gene may affect the safety of this drug. Objective: to analyze associations between the CYP3A5, CYP2C9, CYP2C19, CYP2D6 and ABCB1 gene polymorphisms and the safety of phenazepam treatment for alcohol withdrawal syndrome (AWS). Patients and methods. The investigation enrolled 102 patients diagnosed with uncomplicated AWS (IDC-10 code F10.30). All the patients were followed up for 6 days within which they took phenazepam. 5-ml venous blood samples were collected from each patient for genotyping. The carriage of CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, CYP2C9*2, ABCB1 3435C>T, 1236C>T, and 2677G>T/A polymorphic variants was determined by a real-time polymerase chain reaction assay. Therapy safety was evaluated using the UKU Side-Effect Rating Scale on day 6. Statistical analysis was carried out with SPSS Statistics 21.0. Haplotype and combinatorial analyses were performed using SNPStats. Results and discussion. The greater subjective severity of adverse reactions (ARs) was shown for the homozygotes of ABCB1 1236C>T CC (odds ratio (OR), 2.154; 95% confidence interval (CI), 1.271–3.650; p=0.014) and ABCB1 2677G>T GG (OR, 2.154; 95% CI, 1.271–3.650; p=0.014). On the contrary, a combinatorial analysis revealed the role of ABCB1 3435C>T, 1236C>T, and 2677G>T polymorphic alleles as predictors for the greater subjective severity of ARs. The following statistically significant polymorphic variant combinations were ABCB1 3435-1236–2677 and T-T-T-CYP3A5*3 isozymes (OR=5.03; 95% CI, 1.65–15.34; p=0.0056); T-T-T-CYP2C9*1 (OR=3.61; 95% CI, 1.31–9.92; p=0.015); T-T-T-CYP2C19*1 (OR=2.52; 95% CI, 1.05–6.08; p=0.042). Attention disorders were also established to be associated with the carriage of T-T-T-CYP2D6*1 (OR=2.58; 95 CI, 1.08–6.13; p=0.035). Conclusion. The carriage of ABCB1 3435-2677-1236 (T-T-T) haplotype is significantly associated with the greater severity of ARs in phenazepam-treated patients with AWS.

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis.

CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events and bradycardia. Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding. Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.

Therapeutic Drug Monitoring of Olanzapine and Cytochrome P450 Genotyping in Nonsmoking Subjects.

The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young nonsmoking men treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients. A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. A liquid chromatographic-tandem mass spectrometric method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier real-time polymerase chain reaction system following standard protocols. Evidence indicating that CYP2D6 polymorphism has a significant (P = 0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring (TDM) for olanzapine. TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.

Development of a Physiologically Based Pharmacokinetic Model for Metoprolol in Different CYP2D6 Genotypes

Metoprolol, used in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes alpha‐hydroxylation and O‐demethylation. The genetic polymorphism of CYP2D6 leads to differences in the pharmacokinetics of CYP2D6 substrates. Physiologically based pharmacokinetic (PBPK) modeling is a useful tool for predicting the PK profile of drugs that assess the impact of covariates such as demographics, race, and genetic polymorphism. We tested whether the pharmacokinetics of metoprolol was altered by the different CYP2D6 genotypes in Korean subjects. Then, through in vitro study of metoprolol, the metabolic capacity of metoprolol was measured according to the CYP2D6 genotypes. Finally, we developed the PBPK model of metoprolol related to CYP2D6 genetic polymorphism. Forty‐five volunteers were recruited and grouped as CYP2D6 *wt⁄*wt (*wt=1 or 2, n=15), CYP2D6 *wt⁄*5 (n=4), CYP2D6 *wt/*10 (n=9), CYP2D6 *10⁄*10 (n=10), CYP2D6 *5/*10 (n=5) and CYP2D6 *5/*5 (n=2) according to their genotypes. Metoprolol tartrate 100 mg (Betaloc®) was administered orally once to each subject in these six groups. The CYP2D6*1 and CYP2D6*10 were incubated with 10–2000 μM metoprolol for 20 min at 37 □. Then the metabolites were extracted, and the concentration was analyzed by liquid chromatography‐mass spectrometry. The PBPK modeling of metoprolol was developed and optimized using PK‐sim® software. And, PBPK model validation was conducted by comparing the predicted values with observed values from comparison the pharmacokinetic studies. The AUCinf mean of clinical PK data were 492.96, 673.57, 790.15, 2054.61, 3157.16 and 5152.65 ng·h/ml in CYP2D6 *wt⁄*wt, *wt/*10, *wt⁄*5, *10⁄*10, *5⁄*10 and *5⁄*5, respectively. In vitro study, compared with wild‐type CYP2D6 *1 (100%), the intrinsic clearance (Vmax/Km) values of CYP2D6 *10 (0.33 % for α‐hydroxymetoprolol and 0.41 % for O‐desmethylmetoprolol) were significantly altered. Depending on the physico‐chemical parameters, absorption, distribution, metabolism, excretion (ADME) of each genotype, PBPK model of metoprolol was developed using PK‐sim® software. The AUCinf mean of simulated PK data were 468.01, 646.33, 804.03, 2100.12, 3003.65 and 5677.73 ng·h/ml in CYP2D6 *wt⁄*wt, *wt/*10, *wt⁄*5, *10⁄*10, *5⁄*10 and *5⁄*5, respectively. The developed PBPK model of metoprolol successfully described the pharmacokinetics of each CYP2D6 genotype group and its simulated values were within acceptance criterion (99.998% confidence interval). We developed a PBPK model of metoprolol in relation to genetic polymorphism, which predicts the pharmacokinetics of metoprolol, considering demographic data of subjects, physico‐chemical parameters, ADME properties and CYP2D6 genotypes. These results demonstrate the possibility of metoprolol prescription considering the individual genetic differences through this mechanical approach. Furthermore, the PBPK modeling of metoprolol in CYP2D6 genotypes will be applicable to the treatment of various races, ages, and patients.Support or Funding InformationThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning.The observed and predicted metoprolol pharmacokinetic profiles in CYP2D6*wt/*wt, CYP2D6*wt/*10, CYP2D6*wt/*5, CYP2D6*10/*10, CYP2D6*5/*10 and CYP2D6*5/*5 groups.Figure 1

Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions.

Имплементация системы поддержки принятия решений персонализации режима дозирования бромдигидрохлорфенилбензодиазепина у пациентов с синдромом отмены алкоголя, основанной на фармакогенетических биомаркерах

Введение: Имплементация систем поддержки принятия решений, способных формировать рекомендации по выбору лекарствен- ного средства и его дозы в соответствии с результатами фармакогенетического тестирования, является актуальной задачей, так как решение ее позволит повысить эффективность терапии и снизить риск развития нежелательных лекарственных реакций.Материалы и методы: В исследовании принимал участие 51 пациент (21 - основная группа, получавшая назначения в соответ- ствии с рекомендациями, основанными на результатах фармакогенетического тестирования, а 30 - группа сравнения, получавшая назначения без них) мужского пола с синдромом отмены алкоголя. Для оценки эффективности и безопасности терапии синдрома отмены алкоголя, которую осуществляли с использованием бензодиазепинового транквилизатора феназепама (бромдигидрохлор- фенилбензодиазепина), а также стандартной дезинтоксикационной и витаминотерапии, применялись международные психоме- трические шкалы и шкалы оценки выраженности нежелательных реакций. Определение полиморфизмов генов CYP2D6*4 (1846G&gt;A, rs3892097), CYP2C19*2 (681G&gt;A, rs4244285), CYP2C19*3 (636G&gt;A, rs4986893), CYP2C19*17 (-806C&gt;T, rs12248560), CYP3A5*3 (6986A&gt;G, rs776746) и ABCB1*6 (3435C&gt;T, rs1045642) осуществлялось методом полимеразной цепной реакции в реальном времени с аллель-специфиче- ской гибридизацией. Интерпретацию результатов фармакогенетического тестирования осуществляли с использованием свободно распространяемого программного обеспечения PharmacoGenomeX2 (www.pgx2.com).Результаты: Получены статистически значимые различия в количестве баллов по всем психометрическим шкалам у пациентов основной группы и группы сравнения. Например, по шкале оценки тяжести синдрома отмены алкоголя к 3-му дню исследования количество баллов в основной группе составляло 13,5 [11,2; 16,0], а в группе контроля - 18,0 [17,0; 22,0] (p &lt; 0,001); к 5-му в основ- ной группе - 6,5 [4,2; 8,0], в группе контроля - 15,0 [14,0; 16,0] (p &lt; 0,001). По шкале безопасности UKU также была получена стати- стически значимая разница. К 3-му дню исследования количество баллов по шкале UKU в основной группе составило 6,0 [5,0; 7,0], а в группе контроля - 7,0 [6,0; 8,0] (p = 0,030); к 5-му дню разница возрастала. В основной группе - 5,5 [3,0; 9,0], в группе контроля - 14,0 [12,0; 19,0] (p &lt; 0,001). Группы были репрезентативны (при включении в исследование разница в количестве баллов отсутствовала). Выводы: Персонализация дозы лекарств в соответствии с фармакогенетическими алгоритмами у пациентов с синдромом отмены алкоголя, способна снизить риск развития нежелательных реакций и фармакорезистентности, что позволяет рекомендовать исполь- зование фармакогенетических систем поддержки принятия решений для подбора дозы лекарств. Introduction: Implementation of the clinical decision support systems capable of forming the recommendations on drug and dose selec- tion according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task will allow increasing the efficacy of ther- apy and decreasing the risk of undesirable side effects.Materials and methods: The study involved 51 patients (21 - the main group receiving appointments in accordance with the recommenda- tions based on the results of pharamogenetic testing, and 30 - the comparison control group receiving appointments without them) male with alcohol withdrawal syndrome. In order to assess the effectiveness and safety of alcohol withdrawal syndrome, which was performed with the benzodiazepine tranquilizer of phenazepam (bromodihydrochlorophenylbenzodiazepine), as well as standard detoxification and vitamin therapy, international psychometric scales and scales of assessment in expressions of adverse reactions. Genotyping Determination of genetic polymorphisms CYP2D6*4 (1846G&gt;A, rs3892097), CYP2C19*2 (681G&gt;A, rs4244285), CYP2C19*3 (636G&gt;A, rs4986893), CYP2C19*17 (-806C&gt;T, rs12248560), CYP3A5*3 (6986A&gt;G, rs776746) and ABCB1*6 (3435C&gt;T, rs1045642) were realized using real-time polymerase chain reaction with allele specific hybridization. Interpretation of the results of pharmacogenetic testing was carried out with the help of free soft- ware PharmacoGenomeX2 (www.pgx2.com)Results: Statistically significant differences in the number of scores for all psychometric scales in the patients of the main group and the comparison group were obtained. For example, on the scale of assessing the severity of alcohol withdrawal syndrome by the 3rd day of the study, the score in the main group was 13.5 [11.2; 16,0], and in the control group - 18,0 [17,0; 22.0] (p &lt;0.001); to the 5th in the main group - 6.5 [4.2; 8.0], in the control group - 15.0 [14.0; 16.0] (p &lt;0.001). On the UKU security scale, a statistically significant difference was also obtained. By the 3rd day of the study, the UKU score in the main group was 6.0 [5.0; 7,0], and in the control group - 7,0 [6,0; 8.0] (p = 0.030); by the 5th day the difference increased. In the main group, 5.5 [3.0; 9.0], in the control group - 14.0 [12.0; 19.0] (p &lt;0.001). The groups were representative (when included in the study, the difference in the number of points was absent).Conclusion: Personalization of the dose of drugs in accordance with pharmacogenetic algorithms in patients with alcohol withdrawal syn- drome, can reduce the risk of unwanted reactions and pharmacoresistance, which allows to recommend the use of pharmacogenetic deci- sion support systems for drug dosage selection.

Impact of CYP2D6 Polymorphisms on Propranolol Effects in Children with Portal Hypertension

Impact of CYP2D6 Polymorphisms on Propranolol Effects in Children with Portal Hypertension

Genetic and pharmacogenetic counselling in psychiatric practice

Genetic research in psychiatry has been developing intensively for over 30 years. The social knowledge on the role of genes in the predisposition to diseases and their importance for treatment effects increases. Psychiatric genetic counselling is a service provided under healthcare around the world. The aim of this paper is to present psychiatric genetic counselling, its role for patients and its application in the clinical practice at the current state of knowledge. We discuss these aspects of genetic consultation which relate to mental health. Psychiatric genetic counselling is rarely available in the Polish psychiatric care system and access to specialist training is limited. We indicate that the patient’s adaptation to the genetic burden can bring potential benefits, e.g. better compliance with doctor’s prescriptions. Based on current expert recommendations, we discuss pharmacogenetic tests which are useful in clinical practice. In particular, we analyse the polymorphisms of CYP2D6, CYP2C19 and histocompatibility complex genes HLA.

Фармакогенетика в анестезиологии: на что стоит обратить внимание

Individual pharmacogenetic features of patients areactively studied in various fields of medicine and anesthesiology is no exception. The purpose of this article is to unite the available literature data of polymorphisms affecting the perioperative period. The review includes information obtained from SCOPUS, MedLine, PharmGKB. The effects of cytochrome CYP2D6 polymorphism on the metabolism of tramadol, ondansetron and codeine are described. Also the influence of µ-opioid receptor OPRM1 polimorphism on the doses of narcotic analgesics and ryanodine receptor RYR1 and calcium channels on the probability of malignant hyperthermia are described, and also considered gene polymorphisms that affect the development of anaphylactic reactions

Impact of CYP2D6 Polymorphisms on Tamoxifen Treatment in Patients With Retroperitoneal Fibrosis: A First Step Towards Tailored Therapy?

To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of TMX to more potent endoxifen is dependent on enzyme activity of CYP2D6. CYP2D6 genotyping and phenotype prediction of all patients treated with TMX between 02/2007 and 01/2018 was assessed using multiplex polymerase chain reaction (PCR). Groups were classified by phenotype: extensive (EM) vs poor and intermediate (PM+IM) vs ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including magnetic resonance imaging and positron emission tomography-computed tomography) and health-related quality of life using the SF-36 was performed. A total of 63/194 patients received TMX, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, 8 PM+IM and 3 UM. The median therapy duration was 364.5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17.5%), including all UM patients (P <.001). Magnetic resonance imagings showed a regression of fibrosis for EM and PM+IM in 69% and 62.5% of cases and a progression for UM in 100% (P=.004). In positron emission tomography-computed tomography, glucose utilization of RPF decreased significantly for EM and PM+IM. The physical sum-score of SF-36 improved for EM and PM+IM and decreased for UM (P <.05). The removal of DJ-stents was successful for EM, PM+IM, and UM in 48.3%, 75%, and 0% of cases (P=.0581). Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.

Clinical Relevance of CYP2D6 Polymorphisms in Patients of an Austrian Medical Practice: AFamily Practice-Based Observational Study.

BackgroundAround 20–30% of all prescribed drugs are estimated to be metabolised by the cytochrome P450 (CYP) 2D6 enzyme. In a medical practice, it is usually not known whether a patient is a poor, intermediate, normal or ultra-rapid metaboliser for CYP2D6-metabolised drugs.ObjectiveThis study aims to explore the clinical relevance and the extent of hazardous prescriptions by analysing the metaboliser status of patients already taking such drugs.MethodsThis is a family practice-based observational study performed in a rural practice for general and family medicine in Lower Austria providing care for approximately 2100 patients annually. In 287 consecutive patients, who had taken or were taking a drug metabolised by CYP2D6 during the last 3 years, the metaboliser status was analysed.ResultsThe genetic analysis of 287 patients resulted in 51.22% normal metabolisers, 38.68% intermediate metabolisers, 6.27% poor metabolisers and 3.83% ultra-rapid metabolisers. In 50 cases (poor metaboliser, intermediate metaboliser and ultra-rapid metaboliser, i.e. 17.42% of all tested patients taking a CYP2D6-specific drug), an altered gene function was identified, for which clinical guideline annotations, drug label annotations, or clinical annotations are available. Allele and genotype frequencies were in accordance with data from other European studies.ConclusionsIn 17.42% of all patients already taking a drug metabolised by CYP2D6, knowledge of the genetically defined metaboliser status would have been of immediate clinical relevance before prescribing the drug.ClinicalTrials.gov identifierNCT03859622.Electronic supplementary materialThe online version of this article (10.1007/s40801-019-00177-4) contains supplementary material, which is available to authorized users.

Pharmacogenetic relevant polymorphisms of CYP2C9, CYP2C19, CYP2D6, and CYP3A5 in Bhutanese population.

Background Marked differences among genotype frequencies (Caucasians, Asians, and Africans) have been observed in cytochrome P450 (CYP) genes. Data on the frequency of pharmacogenetic relevant polymorphisms in Bhutanese population is absent. This study aimed to investigate the frequencies of pharmacogenetic relevant polymorphisms of CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), CYP2D6 (*10), and CYP3A5 (*3) in Bhutanese population. Methods Genotyping was performed in 443 DNA samples using polymerase chain reaction-restriction fragment length polymorphism. Results For CYP2C9, allele frequencies of *2 and *3 variants were 0.339% and 0%, respectively. For CYP2C19, frequencies of *2 and *3 variants were 30.135% and 15.689%, respectively. Allele frequencies of CYP2D6*10 and CYP3A5*3 were 21.332% and 77.314%, respectively. Allele frequencies of CYP2C9*2 are similar to most Asians while CYP2C9*3 was absent. CYP2C19*2 showed a close resemblance to Japanese and Burmese, while CYP2C19*3 is near to Japanese and Korean. CYP2D6*10 is noticeably lower than other Asians. CYP3A5*3 is similar to East Asians (Chinese, Japanese, and Korean). Conclusions The Bhutanese population is polymorphic for these CYP genes, except for CYP2C9*3. Similar to other populations, genetic testing for these genes may, therefore, be helpful to obtain the benefit from pharmacological treatments and prevent adverse drug reactions.

Pharmacogenetics biomarkers of antipsychotics’ safety in adolescents with acute psychotic episode

Currently, there is a lack of pharmacogenetic research of antipsychotics’ safety in children and adolescents with acute psychotic episodes. Genetic polymorphisms of CYP2D6 and ABCB1 are the most likely candidates for such studies. AIM.To establish possible associations of CYP3A, CYP2D6, ABCB1 polymorphisms with safety of antipsychotics of an acute psychotic episode in adolescents during the first 14 days of treatment. MATERIALS AND METHODS. We observed 53 adolescents, hospitalized with acute psychotic episode, during 14 days of treatment. Mean age was 15,08±1,7 years. All patients took antipsychotic as the main drug. The tolerance to antipsychotics was assessed using UKU SERS, SAS, BARS. We collected a buccal epitelium from each patient and genotyped CYP3A4*22 (rs2740574), CYP3A5*3 (6986A&gt;G, rs7767746), CYP2D6*4, *10 (rs3892097, rs1065852), ABCB1 1236C&gt;T (rs1128503), 2677G&gt;T/A (rs2032582), 3435C&gt;T (rs1045642) by real-time PCR. RESULTS. Scores of UKU SERS, SAS, BARS, AIMS scales did not correlated with average doses of antipsychotics. Distribution of genetic polymorphisms were in the Hardy-Weinberg equilibrium. The carriage of CYP2D6*4 was associated with the presence of «Asthenia / Lassitude / lncreased Fatigability» (70% vs. 3.6%, p=0.039), the carriage of CYP2D6*10 was associated with «Increased dream activity» (53.8% vs. 22.5%, p=0.043). The «Increased Duration of Sleep» was more often observed in homozygotes according to the polymorphisms ABCB1 2677G&gt;T/A (50% vs. 15.8%, p=0.006) and 3435C&gt;T (41.7% vs. 8.2%, p=0.007). Carriers of TT polymorphism homozygote ABCB1 2677G&gt;T/A also more frequently noted «Polyuria/polydypsia» (37.5% vs. 5.18%, p=0.045). CONCLUSION.Genetic polymorphisms CYP2D6*4, *10, ABCB1 2677G&gt;T/A and 3435C&gt;T increased a risk of adverse drug effects of antipsychotics in adolescents with acute psychotic episode.

PharmVar GeneFocus: CYP2D6.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).