Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays.

Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37–81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-β-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.

In the modern world, there is a rapid advance in the design and clinical introduction of a huge number of drugs that are able to cure a patient or to improve his/her health status on the one hand and to cause significant harm to his/her health on the other. Polypragmasy is the desire to enhance the efficiency of treatment and to help the patient recover from all developed diseases inevitably leads to the use of a large number of medications. At the present time, polypragmasy as a result of iatrogenia is a serious public health problem, as it is clinically manifested by a reduction in the effectiveness of pharmacotherapy, by the development of severe adverse drug reactions, and by a considerable increase in healthcare expenditures. The reason for the simultaneous prescription of multiple drugs may be comorbidity (multimorbidity), the availability of drugs, as well as clinical guidelines, manuals of professional medical associations, treatment standards that contain recommendations for using combination therapy with more than 5 drugs for only one disease in some cases, the efficiency of which corresponds to a high level of evidence. Currently, the fight against polypragmasy is one of the important tasks in rendering medical care to elderly and senile patients since it is a major risk factor of adverse drug reactions in this category of people. To minimize polypragmasy in elderly patients, it is necessary to use current methods for analyzing each prescription of a drug (the index of rational drug prescribing; an anticholinergic burden scale) and those for optimizing pharmacotherapy with the use of restrictive lists (Beers criteria, STOPP/START criteria) that will be able to reduce the number of errors in the administration of drugs and to maximize the efficiency and safety of pharmacotherapy.

Introduction: Although pharmacogenetic tests provide the information on a genotype and the predicted phenotype, these tests themselves do not provide the interpretation of data for a physician. There are currently approximately two dozen pharmacogenomic clinical decision support systems used in psychiatry. Implementation of clinical decision support systems capable of forming recommendations on drug and dose selection according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task may allow increasing the efficacy of therapy and decreasing the risk of undesirable side effects. Materials and methods: The study included 51 male patients (21 in the main group and 30 in the control group) with alcohol withdrawal syndrome. To evaluate the efficacy and safety of therapy, several international psychometric scales and rating scales to measure side effects were used. Genotyping was performed using real‐time polymerase chain reaction with allele‐specific hybridization. Pharmacogenetic test results were interpreted using free software PGX2 ( www.pgx2.com ). Results: Statistically significant differences between the scores derived from all psychometric scales were revealed. For instance, the total score on CIWA‐Ar scale by day 3 was 13.5 [11.2; 16.0] for the main group and 18.0 [17.0; 22.0] ( p < 0.001) for the control group; by day 5, it was 6.5 [4.2; 8.0] for the main group and 15.0 [14.0; 16.0] ( p < 0.001) for the control group. The UKU side effect rating scale (UKU) also revealed a statistically significant difference. The total score on UKU scale by day 3 was 6.0 [5.0; 7.0] for the main group and 7.0 [6.0; 8.0] ( p < 0.001) for the control group; by day 5, this difference grew significantly: 5.5 [3.0; 9.0] for the main group and 14.0 [12.0; 19.0] ( p < 0.001) for the control group. The groups were representative (there was no difference between the scores at the inclusion of patients). Conclusion: Pharmacogenetic‐guided personalization of drug dose in patients with alcohol withdrawal syndrome can reduce the risk of undesirable side effects and pharmacoresistance. It allows recommending the use of pharmacogenomic clinical decision support systems for optimizing drug dosage.