CYP2C19 Gene Research Articles

The Frequency and Structure of Adverse Drug Reactions in the Pharmacotherapy of Epilepsy

The problem of the safety of antiepileptic therapy due to the duration of treatment and the need for regular intake of antiepileptic drugs (AEDs) is extremely significant. Adverse reactions (ADRs) may outweigh any positive effect of therapy associated with seizure reduction. The purpose of the study: to analyze the frequency and structure of ADRs of AEDs. Materials and Methods: The work was carried out within the framework of comprehensive research on the topic No. 210-16 "Epidemiological, genetic and neurophysiological aspects of diseases of the nervous system (central, peripheral and vegetative) and preventive medicine" (registration number 0120.0807480). Results: The frequency of ADRs against the background of third-generation AEDs was not inferior to that against the background of receiving second-generation AEDs, while the structure of ADRs was different: third-generation AEDs had a higher incidence of ADRs from the central nervous system, including a worsening of the course of epilepsy. The ratio of the chances of valproic acid accumulation with the achievement of toxic concentration in the blood and the development of un-desirable side effects in poor metabolizers (carriers of the polymorphism of CYP2C9*2 or CYP2C9*3) the gene encoding the cytochrome P450 isoenzyme 2C9 of the liver is 5.94 and 4.27, respectively. Conclusion: A personalized approach to ensuring the safety of valproic acid preparations based on taking into account the carriage of polymorphisms of the CYP2C9 gene allows to reduce the incidence of ADRs in patients receiving valproic acid preparations from 59.28% to 10.78%. The introduction of a personalized approach to the administration of valproates to patients suffering from epilepsy in the Krasnoyarsk Territory did not lead to an increase in direct costs.

Effects of the EM CYP2C19 type and MDR1 3435CC gene on Helicobacter pylori eradication rate in patients with duodenal ulcer by the four-drug regimen of rabeprazole, bismuth, tetracycline, and tinidazole

Background: The MDR1 genotype and the CYP2C19 phenotype determine how much PPI is absorbed from the gut and how much is processed in the liver. Objective: To assess the impact of CYP2C19 and MDR1 C3435T gene polymorphisms on the efficiency of H. pylori eradication treatment with a 4-drug regimen of rabeprazole, bismuth, tetracycline, and tinidazole (RBTT) in patients with duodenal ulcers. Methods: The study was conducted at Can Tho University of Medicine and Pharmacy. Gene polymorphisms for CYP2C19 and MDR1 C3435T were detected through a blood test. The RBTT 4-drug regimen was used to eradicate H. pylori. Results: The success rate of the RBTT regimen for eradicating H. pylori in female patients with the CYP2C19 EM phenotype + MDR1 3435CC genotype was 20.0% lower than the rate of 91.7% for the group without both phenotype and genotype (p = 0.01, OR = 0.02, 95%CI: 0.00–0.45). Conclusion: Compared to the group lacking both phenotypes and genotypes, female patients with the CYP2C19 EM phenotype + MDR1 3435CC genotype had a lower rate of H. pylori eradication by RBTT regimen.

Precision dosing for patients on tricyclic antidepressants.

We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect. The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs. The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect. To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion.

Aiming for precision: CYP2C19 gene polymorphism and clopidogrel resistance in patients with peripheral artery disease

Aiming for precision: CYP2C19 gene polymorphism and clopidogrel resistance in patients with peripheral artery disease

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Genetic Determinants of Response to Statins in Cardiovascular Diseases.

Despite extensive efforts to identify patients with cardiovascular disease (CVD) who could most benefit from the treatment approach, patients vary in their benefit from therapy and propensity for adverse drug events. Genetic variability in individual responses to drugs (pharmacogenetics) is considered an essential determinant in responding to a drug. Thus, understanding these pharmacogenomic relationships has led to a substantial focus on mechanisms of disease and drug response. In turn, understanding the genomic and molecular bases of variables that might be involved in drug response is the main step in personalized medicine. There is a growing body of data evaluating drug-gene interactions in recent years, some of which have led to FDA recommendations and detection of markers to predict drug responses (e.g., genetic variant in VKORC1 and CYP2C9 genes for prediction of drug response in warfarin treatment). Also, statins are widely prescribed drugs for the prevention of CVD. Atorvastatin, fluvastatin, rosuvastatin, simvastatin, and lovastatin are the most common statins used to manage dyslipidemia. This review provides an overview of the current knowledge on the pharmacogenetics of statins, which are being used to treat cardiovascular diseases.

Comparison of the Efficacy and Safety of Cyp2c19 Gene-guided Oral Administration of Different P2Y12 Inhibitors in Elderly Patients with Acute Coronary Syndrome

Objective To explore the survival prognosis and safety analysis of the cyp2c19 gene-guided ACS elderly patient group using Tegretol and Clopidogrel. Methods Three hundred and eighty-five ACS patients aged ≥65 years were selected, tested for polymorphisms in the cyp2c19 gene, and divided into two groups according to the oral P2Y12 receptor inhibitor: 320 patients in the clopidogrel group and 165 patients in the tegretol group. Patients were followed up for 1 year after discharge from the hospital, with the primary end point being a composite end point of adverse cardiovascular events including cardiac death, nonfatal infarction, or absence of stroke, and the secondary end point including unstable angina, in-stent stenosis, target vessel revascularization, and all-cause mortality, as well as bleeding events. Results The 1-year rate of ischemic events was lower in patients treated with tegretol compared with the clopidogrel group [28.5% (47/165) versus 26.3% (84/320), P = 0.599], and the difference in the 1-year rate of BARC 2, 3, and 5 events between the two groups was not statistically significant [6.0% (10/165) versus 3.4% (11/320), P = 0.179]. P = 0.179]. Conclusion In elderly patients with cyp2c19-directed ACS, there was no significant difference in survival prognosis, ischemic events, or bleeding risk between tegretol and clopidogrel at 1 year.

Genetic Variants of CYP2C8 Gene Predisposition to Type 2 Diabetes Risk

Background: Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels due to insulin resistance or inadequate insulin secretion from pancreatic beta cells. The mitochondrial CYP2C8 gene, located on chromosome 10q24, encodes cytochrome P450 and spans 37 kb with nine exons. Genetic variants in this gene may influence T2DM susceptibility. Method: This study aimed to investigate the association between genetic polymorphisms in the CYP2C8 gene (rs1934953 and rs1934952) and the risk of T2DM in Iraqi patients. Blood samples were collected from 48 participants, including 24 T2DM patients and 24 healthy controls. DNA extraction, polymerase chain reaction (PCR), and sequencing were performed to analyze genetic variations. Statistical analysis was conducted using chi-square tests, logistic regression, and Hardy-Weinberg equilibrium calculations. Results: Analysis revealed that the rs1934953 variant in the CYP2C8 gene was associated with T2DM, with the A allele showing a protective effect (odds ratio: 0.840, 95% confidence interval: 0.780-0.904, P=3.04×10-6). Additionally, an interaction effect between rs1934953 in CYP2C9 and rs12766752 in CYP2C8 on T2DM risk was observed (P=0.003). Furthermore, rs1934953 showed significant association with high-density lipoprotein cholesterol (HDL-C). At the rs1934952 C/T locus, a transition type genetic mutation was detected, with the TT genotype considered a risk factor for T2DM, while the CC and CT genotypes were protective. The Hardy-Weinberg probability value for the patient group was 0.0321, indicating notable discrepancies in genotype distribution, while the healthy group showed no significant differences (Hardy probability: 0.2001). The TT genotype at rs1934953 was associated with a decreased risk of T2DM, while the CC and CT genotypes were potential risk factors. Conversely, at rs1934952, the CC and CT genotypes were protective against T2DM, while the TT genotype was associated with increased risk. Conclusion: in conclusion, the study indicates that there may be links between CYP2C8 gene variances and an increased chance of type 2 diabetes in Iraqi patients.

From genes to drugs: CYP2C19 and pharmacogenetics in clinical practice.

The CYP2C19 gene is frequently included in different pharmacogenomic panels tested in clinical practice, due to its involvement in the metabolism of a myriad of frequently prescribed medications. Accordingly, CYP2C19 genotyping can promote precise therapeutic decisions and avoid the occurrence of significant drug-drug-gene interactions in the clinical setting. A comprehensive examination of the role of the CYP2C19 gene in real-world medical settings is presented in this review. This review summarizes the most recent information on how genetic variants in CYP2C19 affect drug metabolism and therapeutic outcomes. It goes into the wide range of CYP2C19 phenotypes, with different degrees of metabolizing activity, and their implications for customized medication response through a review of the literature. The review also analyzes the clinical significance of CYP2C19 in several medical specialties, including cardiology, psychiatry, and gastro-enterology clinics, and illuminates how it affects pharmacological efficacy, safety, and adverse effects. Finally, CYP2C19-supported clinical decision-making is outlined, highlighting the possibility of improving therapeutic outcomes and achieving more affordable treatment options, a step towards optimizing healthcare provision through precision medicine.

A novel AllGlo probe-quantitative PCR method for detecting single nucleotide polymorphism in CYP2C19 to evaluate the antiplatelet activity of clopidogrel

CYP2C19 gene has multiple single nucleotide polymorphism (SNP), which is the major determinant for clopidogrel treatment responses. Therefore, CYP2C19 SNP detection is essential for predicting clopidogrel efficacy. Currently, there is still no quick and effective method for routine detection of common CYP2C19 SNPs in clinical laboratories, which is critically needed prior to clopidogrel treatment. AllGlo™ based quantitative PCR was used to develop a novel genotyping method for CYP2C19 SNP detection, termed CyPAllGlo. The performance of CyPAllGlo was compared with that of the commonly used fluorescence in situ hybridization (FISH) method, and the data was verified by DNA sequencing. CyPallGlo was used to identify CYP2C19 polymorphisms in 363 patients with coronary heart disease. The univariate analysis was used to access the antiplatelet efficacy of clopidogrel in patients. The associations between CYP2C19 polymorphisms and clopidogrel efficacy were analyzed. Using CyPAllGlo to detect CYP2C19*2 and CYP2C19*3 alleles was highly specific and fast. The detection limit was approximately 0.07 µg/µl and 0.7 µg/µl for CYP2C19*2 and CYP2C19*3, respectively. The consistency between FISH and CyPAllGlo were 98.07% for CYP2C19*2 and 99.17% for CYP2C19*3. DNA sequencing showed that the accuracy of CyPAllGlo was 100%. The analysis time for the whole CyPAllGlo procedure was approximately 60 min. Univariate analysis showed that the anticoagulation efficacy of clopidogrel was related to patient age, CYP2C19 genotype, metabolic phenotype, and LDL level. The logistic regression analysis showed that the genotype of CYP2C19 and metabolic phenotype was the two risk factors for clopidogrel antiplatelet ineffectiveness. This novel CyPAllGlo is a rapid and accurate method for detection of CYP2C19 SNP. The specificity and consistency of CyPAllGlo are comparable with that of widely used DNA sequencing. These findings provide valuable rapid method for predicting clopidogrel efficacy, which can be quickly translated to improve personalized precision medicine for coronary heart disease treatment.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Convenient two-step method constructed silicon-based microfluidic chip for fast CYP2C19 SNPs detection.

The rapid detection of single nucleotide polymorphisms (SNPs) in the CYP2C19 gene is crucial for precise clopidogrel usage. Quantitative real-time polymerase chain reaction (qPCR), as a powerful amplification tool, has been widely employed for CYP2C19 SNPs detection. However, traditional qPCR suffers from long amplification times and high reagent consumption. To address these challenges, this work presents a microfluidic SNPs detection device based on on-chip qPCR. The device includes a rapid thermal cycling system, an optical detection system, a control system, and a complementary silicon-glass chip for CYP2C19 SNPs detection. Compared to commercial qPCR instruments that take 1 hour for testing, this device completes the test in just 15 minutes (40 PCR cycles). The resulting linearity is similar to that found using commercial qPCR instruments but with higher amplification efficiency. Additionally, compared with other silicon-based qPCR chips, this chip is constructed by using a convenient two-step method and offers low manufacturing costs, which potentially reduces single-test costs to an acceptable level. This makes our chip promising for point-of-care testing (POCT).

A study on CYP2C9 polymorphism in Puerto Rican Alzheimer's Patients and its role in the Pharmacokinetics of ∆-9-tetrahydrocanna-binol

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects over 55 million people worldwide. Individuals with AD are often prescribed multiple medications to manage comorbidities, many of which are metabolized by enzymes from the cytochrome P450 (CYP). CYP2C9 is expressed by the CYP2C9 gene. The highly polymorphic gene is grouped into phenotypes such as poor, intermediate, normal, and ultra-rapid metabolizers that influence the pharmacokinetics (PK) of drugs and their metabolites. Among humans, CYP2C9 is one of the most essential enzymes for metabolizing drugs, including delta-9-tetrahydrocannabinol (THC). The enzyme converts THC into its active metabolite 11-hydroxy-delta-9-THC (OH-THC). IGC-AD1 is a formulation with two active pharmaceutical ingredients, delta-9-THC and melatonin. The Phase 1, multiple ascending dose (MAD) trial, was conducted on a Puerto Rican population. The participant population in the trial (N=13) was 69.2% female and 30.8% male, with an average age of 80.18 (SD+/- 6.22). We report on the effect of CYP2C9 polymorphisms on the pharmacokinetics (PK) of THC and its active metabolite in AD patients from a Phase 1 trial. Using a Mass ARRAY Analyzer 4 Instrument (Invitae Inc.), we determined the following CYP2C9 alleles: *2, *3, *4, *5, *6, *8, *11, *13, *15, and found that 60% of participants (N=6) were carriers of at least one polymorphism including 1*/2* and 1*/3*. The participants with intermediate metabolizers (*1/*3 and *1/*2) showed an increased half-life of THC and OH-THC with major differences between the two intermediate metabolizer groups *1/*3 and *1/*2. In the trial more females were noted to be intermediate metabolizers than males. As polymorphisms of CYP2C9 affect the PK of THC and its metabolite, larger studies are needed to establish PK baselines for polymorphisms of CYP2C9. In the meantime, it is recommended that researchers exercise caution while dosing AD patients with THC.

Effects of trichlorfon on ecotoxicological biomarkers in farmed Colossoma macropomum (tambaqui).

Producers of fish have been looking for viable alternatives for the management of Colossoma macropomum (tambaqui) in confinement systems in order to avoid the harm and subsequent losses caused by parasitic diseases. One alternative used by farmers is pesticides, such as trichlorfon, which has a genotoxic effect. Thus, this study aimed to evaluate the changes in gene expression due to the side effects of trichlorfon in tambaqui. Two treatments were used based on LC50-96h of 0.870 mg/L using 30% and 50% trichlorfon with exposure periods of 48, 72 and 96 h. For differential expression of the genes in the liver, real-time PCR was performed for the AChE, GST, CYP2J6, CYP2C8, 18S and GAPDH genes. After 96 h of exposure to trichlorfon, an alteration in the gene expression profile of the antioxidant defense system (GST) of the tambaqui was observed. It was also observed that this organophosphate did not affect the expression of genes related to the isoenzymes that are responsible for the biotransformation of xenobiotics in phase I (2J6 and 2C8) and cholinesterase AChE. It was concluded that the reduction in gene expression of GST suggests a decrease in metabolization capacity in phase II.

Impact of CYP2C19 gene polymorphisms on clinical outcomes in patients with myocardial infarction during 60 months of follow-up

Objective: To evaluate the effect of CYP2C19 gene polymorphisms on clinical outcomes in patients after successful revascularization for acute myocardial infarction with and without ST segment elevation during clopidogrel therapy for 60 months of follow-up.Methods: From 2011 to 2012, 363 patients with acute myocardial infarction who underwent coronary revascularization were included in the study. In the postoperative period, the patients underwent genetic analysis for the CYP2C19 gene polymorphism. All patients received dual antiplatelet therapy with aspirin and clopidogrel. The 60-month follow-up period assessed the primary composite endpoint of the cumulative incidence of all-cause mortality, recurrent myocardial infarction, and stroke.Results: At 60 months after the initial intervention, 71 patients had a composite primary endpoint event (all-cause death, recurrent myocardial infarction, or stroke): 50 (20%, 95% CI 16–25) in the group patients with "wild genotype" and 21 patients of the "loss of function (LOF) *2+*3" group (19%, 95% CI 13–27). No significant relationship was observe between carriage of LOF alleles of the CYP2C19 and the primary endpoint during the 60-month follow-up (HR 0.99, 95% CI 0.59–1.65, P = .965), as well as between carriage of the homozygous CYP2C19 variant (*2/*2) and the development of myocardial infarction during the same period (HR 1.26, 95% CI 0.30–5.20, P = .752).Conclusion: No correlation was observed between the CYP2C19 gene polymorphisms (*2, *3 alleles) and the incidence of ischemic events in patients with myocardial infarction after myocardial revascularization throughout a 60-month follow-up period. Received 27 November 2022. Revised 25 September 2023. Accepted 26 September 2023. Funding: The study did not have sponsorship. Conflict of interest: The authors declare no conflict of interest. Contribution of the authorsConception and study design: I.O. GrazhdankinData collection and analysis: I.O. GrazhdankinStatistical analysis: V.L. LukinovDrafting the article: I.O. Grazhdankin, A.A. Prokhorikhin, V.I. Baystrukov, E.I. Kretov, V.L. LukinovCritical revision of the article: A.M. ChernyavskiyFinal approval of the version to be published: I.O. Grazhdankin, A.A. Prokhorikhin, V.I. Baystrukov, E.I. Kretov, A.M. Chernyavskiy, V.L. Lukinov

A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals

Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1.

Identification of cytochrome P450 2C18 and 2C76 in tree shrews: P450 2C18 effectively oxidizes typical human P450 2C9/2C19 chiral substrates warfarin and omeprazole with less stereoselectivity

Cytochromes P450 (P450s or CYPs), especially the CYP2C family, are important drug-metabolizing enzymes that play major roles in drug metabolism. Tree shrews, a non-rodent primate-like species, are used in various fields of biomedical research, notably hepatitis virus infection; however, its drug-metabolizing enzymes have not been fully investigated. In this study, tree shrew CYP2C18, CYP2C76a, CYP2C76b, and CYP2C76c cDNAs were identified and contained open reading frames of 489 or 490 amino acids with high sequence identities (70–78 %) to human CYP2Cs. Tree shrew CYP2C76a, CYP2C76b, and CYP2C76c showed higher sequence identities (79–80 %) to cynomolgus CYP2C76 and were not orthologous to any human CYP2C. Phylogenetic analysis revealed that tree shrew CYP2C18 and CYP2C76s were closely related to rat CYP2Cs and cynomolgus CYP2C76, respectively. Tree shrew CYP2C genes formed a gene cluster similar to human CYP2C genes. All four tree shrew CYP2C mRNAs showed predominant expressions in liver, among the tissue types examined; expression of CYP2C18 mRNA was also detected in small intestine. In liver, CYP2C18 mRNA was the most abundant among the tree shrew CYP2C mRNAs. In metabolic assays using human CYP2C substrates, all tree shrew CYP2Cs showed metabolic activities toward diclofenac, R,S-omeprazole, paclitaxel, and R,S-warfarin, with the activity of CYP2C18 exceeding that of the other CYP2Cs. Moreover, tree shrew CYP2C76 enzymes metabolized progesterone more efficiently than human, cynomolgus, or marmoset CYP2Cs. Therefore, these novel tree shrew CYP2Cs are expressed abundantly in liver, encode functional enzymes that metabolize human CYP2C substrates, and are likely responsible for drug clearances.

Novel Cytochrome P450 2C119 Enzymes in Cynomolgus and Rhesus Macaques Metabolize Progesterone, Diclofenac, and Omeprazole.

Cynomolgus and rhesus macaques are used in drug metabolism studies due to their evolutionary and phylogenetic closeness to humans. Cytochromes P450 (P450s or CYPs), including the CYP2C family enzyme, are important endogenous and exogenous substrate-metabolizing enzymes and play major roles in drug metabolism. In cynomolgus and rhesus macaques, six CYP2Cs have been identified and characterized, namely, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2C76, and CYP2C93. In this study, CYP2C119, a new CYP2C, was identified and characterized in cynomolgus and rhesus macaques. Cynomolgus and rhesus CYP2C119 contained open reading frames of 489 amino acids with high sequence identities to human CYP2C8 and to cynomolgus and rhesus CYP2C8. Phylogenetic analysis showed that cynomolgus and rhesus CYP2C119 were closely related to cynomolgus and rhesus CYP2C8. In cynomolgus and rhesus genomes, CYP2C genes, including CYP2C119, form a cluster. Among the tissues analyzed, cynomolgus CYP2C119 mRNA was predominantly expressed in liver. Hepatic expressions of CYP2C119 mRNA in four cynomolgus and two rhesus macaques varied, with no expression in one rhesus macaque. Among the CYP2C mRNAs, CYP2C119 mRNA was expressed less abundantly than CYP2C8, CYP2C9, CYP2C19, and CYP2C76 mRNAs but more abundantly than CYP2C18 mRNA. Recombinant cynomolgus and rhesus CYP2C119 catalyzed progesterone 16α-, 17α-, and 21-hydroxylation and diclofenac and omeprazole oxidations, indicating that CYP2C119 is a functional enzyme. Therefore, the novel CYP2C119 gene, expressed in macaque liver, encodes a functional enzyme that metabolizes human CYP2C substrates and is likely responsible for drug clearances. SIGNIFICANCE STATEMENT: Cytochrome P450 2C119 was found in cynomolgus and rhesus macaques, in addition to the known P450 2C8, 2C9, 2C18, 2C19, 2C76, and 2C93. Cynomolgus and rhesus CYP2C119 contain open reading frames of 489 amino acids with high sequence identity to human CYP2C8. Cynomolgus CYP2C119 mRNA is predominantly expressed in the liver. Recombinant CYP2C119 catalyzed progesterone hydroxylation and diclofenac and omeprazole oxidations. Therefore, the novel CYP2C119 gene expressed in the macaque liver encodes a functional enzyme that metabolizes human CYP2C substrates.

Tailoring Antithrombotic Regimens for Percutaneous Coronary Intervention Patients with High Bleeding and Ischemic Risk (TAILOR-BIRISK): Individualized Management and Genotype-Guided De-escalation.

Percutaneous coronary intervention (PCI) is a widely used reperfusion strategy for coronary artery disease, with millions of procedures performed annually. Attention has recently been drawn to a unique population, known as "bi-risk" patients, who have high ischemic and high bleeding risks and undergo PCI. However, there is currently no established definition or optimal antithrombotic therapy for this group. Genotype-guided antithrombotic therapy, which uses cytochrome P450 (CYP) 2C19 gene testing, may offer a more personalized and precise approach. Nevertheless, recent research has shown that routine genetic testing to guide treatment in the PCI population does not improve patient outcomes, preventing it from being routinely recommended in guidelines. This review proposes, for the first time, the definition of the bi-risk population and the concept of TAILOR-BIRISK for their treatment strategies. TAILOR-BIRISK emphasizes de-escalating antithrombotic treatment and suggests that a short course of dual antiplatelet therapy (DAPT) followed by monotherapy by either clopidogrel or ticagrelor 60 mg BID (BID, twice daily) could be a reasonable option for this population. Additionally, the use of CYP2C19 gene testing to guide inhibitor selection can help better individualize and customize the antithrombotic regimen. However, more large-sample randomized control studies should be conducted to further explore the optimal antithrombotic strategy for the bi-risk population.

ВСТРЕЧАЕМОСТЬ АЛЛЕЛЕЙ И ГЕНОТИПОВ ПО АЛЛЕЛЬНЫМ ВАРИАНТАМ CYP2С9*2 И CYP2С9*3 СРЕДИ БОЛЬНЫХ С БОЛЕВЫМ СИНДРОМОМ, ПРИНИМАВШИХ НЕСТЕРОИДНЫЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА

Abstract. Introduction. The most clinically significant polymorphic markers of the CYP2C9 gene are the amino acid substitutions of CYP2C9*2. One of the human cytochrome P450 types, i.e., cytochrome CYP2C19, is essential to the metabolism of some drugs, including proton pump inhibitors. Genetic polymorphism of СУР2С19 has some pronounced interindividual differences. Significance of genetic polymorphism is detected where the occurrence of variant alleles exceeds 1% in the population. Aim of the study was to improve the principles of pharmacotherapy with nonsteroidal anti-inflammatory drugs, as related to the frequency of alleles and genotypes on the allelic variants of CYP2С9*2 and CYP2С9*3 in pain syndrome patients taking nonsteroidal anti-inflammatory drugs. Materials and Methods. The study included 69 patients with pain syndrome. Association between being the carrier of genotypes on the CYP2С9*2 and CYP2С9*3 alleles and developing gastropathies as reactions to administering anti-inflammatory drugs was investigated by conducting a prospective case-control study. Molecular genetic testing was performed based on the Laboratory of Medical Genetics of the Research Institute of Hematology and Blood Transfusion at the Ministry of Health of the Republic of Uzbekistan. Results and Discussion. No statistically significant differences were found in the frequencies of the CYP2C9 and CYP2C19 alleles between the groups of patients with and without adverse gastrointestinal reactions to administering nonsteroidal anti-inflammatory drugs or proton pump inhibitors. Conclusions. Our findings allow us to suggest that being a carrier of the allelic CYP2C9*2 and CYP2C9*3 variants should be considered as a gastropathy risk factor of using nonsteroidal anti-inflammatory drugs. It can be assumed that, to reduce the risk of adverse reactions developed in the patients of this category to nonsteroidal anti-inflammatory drugs, the latter ones need a concomitant administration with proton pump inhibitors. It is necessary to continue studying the frequencies of the alleles and genotypes on allelic CYP2С9*2 and CYP2С9*3 variant sin pain syndrome patients taking nonsteroidal anti-inflammatory drugs.