Cytochrome P-450 CYP2C19

细胞色素 P - 450 CYP2C19
  • 文章类型: Journal Article
    阿司匹林和P2Y12受体抑制剂的双重抗血小板治疗(DAPT)(氯吡格雷,普拉格雷,或替格瑞洛)在经皮冠状动脉介入治疗(PCI)后可降低动脉粥样硬化血栓形成事件的风险。大约30%的美国人患有CYP2C19无功能等位基因,这降低了氯吡格雷的有效性。但不是普拉格雷或替格瑞洛,在PCI之后。通过将CYP2C19基因分型整合到临床治疗中,我们已经显示出改善的结果,以指导CYP2C19无功能等位基因携带者中普拉格雷或替格瑞洛的选择。然而,患者特定人口统计的影响,临床,和其他遗传因素对基因型指导的DAPT结局的影响尚未确定。此外,在没有CYP2C19无功能等位基因的患者中,基因型引导的普拉格雷或替格瑞洛降至氯吡格雷的影响尚未在不同的患者中进行研究,真实世界的临床设置。经皮冠状动脉介入治疗后的精确抗血小板治疗(PrecisionPCI)注册是美国多中心注册的患者接受PCI和临床CYP2C19测试。登记处正在招募多样化的人口,评估超过12个月的动脉粥样硬化血栓形成和出血事件,收集DNA样本,并对一部分患者进行血小板功能检测。该注册表旨在通过CYP2C19指导的DAPT定义非洲血统和其他患者特定因素对临床结果的影响。在现实环境中评估CYP2C19引导的DAPT降级在PCI后的安全性和有效性,并确定PCI后氯吡格雷反应的其他遗传影响,最终目标是建立个体化抗血小板治疗的最佳策略,以改善多样化的结果,现实世界的人口。
    Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no-function allele carriers. However, the influence of patient-specific demographic, clinical, and other genetic factors on outcomes with genotype-guided DAPT has not been defined. In addition, the impact of genotype-guided de-escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no-function allele has not been investigated in a diverse, real-world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19-guided DAPT, evaluate the safety and effectiveness of CYP2C19-guided DAPT de-escalation following PCI in a real-world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real-world population.
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  • 文章类型: Journal Article
    背景:同时使用氯吡格雷和质子泵抑制剂(PPI)很常见,但PPI可能降低经皮冠状动脉介入治疗(PCI)患者氯吡格雷的抗血小板作用.我们评估了PPI使用对PCI术后患者临床结局的影响,通过纳入P2Y12反应单元(PRU)和CYP2C19基因分型结果。
    方法:来自接受PCI联合药物洗脱支架植入术并接受氯吡格雷双联抗血小板治疗(DAPT)的患者的多中心登记,在PCI时接受PPI治疗的患者(PPI使用者)与未接受PPI治疗的患者(非使用者)进行比较.主要结果包括全因死亡,心肌梗塞,支架内血栓形成,或12个月的脑血管意外。大出血(出血学术研究联盟[BARC]类型3-5)和胃肠道(GI)出血(BARC类型3-5)是重要的次要结果。使用1:1倾向评分(PS)匹配和竞争风险分析比较调整后的结果。
    结果:在13,160名患者中,2235(17.0%)是处方PPI,平均年龄为65.4岁。PPI使用者的治疗中PRU水平高于非使用者。PS匹配后,主要结局发生在PPI使用者的51例患者中(累积发生率,4.7%)和41例非使用者患者(累积发生率,3.7%;对数秩p=0.27)。在两个CYP2C19功能丧失等位基因的携带者中,PPI的使用与主要结局的风险增加有关(风险比,3.22;95%置信区间,1.18-8.78)。PS匹配队列中PPI使用者和非使用者的大出血和消化道出血(BARC3-5型)发生率相当。
    结论:在接受基于氯吡格雷的DAPT的PCI术后患者中,PPI使用与不良心脑血管事件的风险增加无关。但治疗中PRU有少量但显著的增加.使用更个性化方法的未来研究将进一步阐明这些相互作用并指导循证临床实践。
    BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results.
    METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis.
    RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort.
    CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.
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  • 文章类型: Journal Article
    药物基因组学(PGx)研究遗传学对药物反应的影响,为个性化医疗保健提供量身定制的治疗方法。这项研究评估了使用四种不同的计算工具和各种测序深度的全基因组测序对六种基因进行基因分型的准确性。还探索了使用不同参考基因组(GRCh38和GRCh37)和序列比对(BWA-MEM和Bowtie2)的效果。结果表明,大多数基因的工具性能通常存在较小的差异;然而,在复杂CYP2D6基因的分析中观察到更显著的差异.Cyrius,CYP2D6专用工具,展示了最强大的性能,在所有情况下实现CYP2D6的最高一致率,在大多数情况下,与共识方法相当。具有20倍覆盖深度的样本与具有较高深度的样本之间存在相当小的差异,但是在较低的深度表现下降更明显,特别是在5×此外,当使用相同的方法将样品与不同的参考基因组比对时,观察到CYP2D6结果的变化,或者使用不同的对齐器对相同的基因组,这导致在一些情况下报告不正确的罕见恒星等位基因。这些发现为选择最佳的PGx工具和方法提供了信息,并表明采用两种或多种工具的共识方法对于某些基因和工具组合可能更可取。尤其是在较低的测序深度,确保结果准确。此外,我们展示了上游对齐如何影响工具的性能,一个需要考虑的重要因素。
    Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA-MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6-specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account.
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  • 文章类型: Journal Article
    精确估计患者的药物代谢能力对于抗癫痫剂量个性化很重要。
    量化与编码药物代谢酶的基因变体相关的抗癫痫药物的血浆浓度差异。
    PubMed,临床试验注册。欧盟,ClinicalTrials.gov,国际临床试验注册平台,和CENTRAL数据库在1990年1月1日至2023年9月30日的研究中进行了筛选,没有语言限制.
    两名评审员进行了独立的研究筛选,并评估了以下纳入标准:进行了适当的基因分型,基于基因型的分类为亚组是可能的,每个亚组至少有3名参与者.
    遵循流行病学观察性研究(MOOSE)指南的荟萃分析进行数据提取和后续质量,有效性,和偏见风险评估。纳入研究的结果与随机效应荟萃分析进行汇总。
    用浓度-时间曲线下的剂量归一化面积对抗癫痫药物的血浆浓度进行定量,剂量归一化的稳态浓度,或标准剂量和采样时间单剂量后的浓度。通过将药物遗传学变体的载体和非载体的平均药物血浆浓度除以计算平均值的比率。
    来自98项研究的数据,涉及12543名接受苯妥英治疗的成年参与者,丙戊酸盐,拉莫三嗪,或卡马西平进行了分析。研究主要在东亚(69项研究)或白人或欧洲(15项研究)队列中进行。与参考亚组相比,观察到苯妥英的血浆浓度显着增加,CYP2C9中间代谢者的46%(95%CI,33%-61%),CYP2C19中间代谢物的20%(95%CI,17%-30%),CYP2C19代谢不良者为39%(95%CI,24%-56%);丙戊酸盐,CYP2C9中间代谢者的12%(95%CI,4%-20%),CYP2C19中间代谢者的12%(95%CI,2%-24%),CYP2C19代谢不良者占20%(95%CI,2%-41%);卡马西平,CYP3A5代谢不良者的12%(95%CI,3%-22%)。
    这项系统评价和荟萃分析发现,CYP2C9和CYP2C19基因型编码低酶容量与苯妥英血浆浓度的临床相关增加有关,几种药物遗传学变异与丙戊酸盐和卡马西平血药浓度的统计学显著相关,但仅有轻微的临床相关变化,许多药物遗传学变异与抗癫痫药物的血浆浓度无统计学显著差异。
    UNASSIGNED: Precise estimation of a patient\'s drug metabolism capacity is important for antiseizure dose personalization.
    UNASSIGNED: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.
    UNASSIGNED: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.
    UNASSIGNED: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.
    UNASSIGNED: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.
    UNASSIGNED: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.
    UNASSIGNED: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.
    UNASSIGNED: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.
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  • 文章类型: Journal Article
    背景:目前越南儿童中基于抗菌药物敏感性的幽门螺杆菌根除治疗效率较低。有治疗失败的原因,在宿主遗传因素中,MDR1C3435T和CYP2C19会影响质子泵抑制剂的吸收和代谢-这是根除治疗的关键组成部分。本研究旨在探讨MDR1C3435T和CYP2C19基因多态性对治愈率的影响。
    方法:207例感染幽门螺杆菌的胃炎和消化性溃疡的儿科患者完成了基于质子泵抑制剂埃索美拉唑对抗菌药物敏感性的根除治疗。至少4周后通过脲酶呼气试验评估根除功效。使用基于Sanger原理的测序方法确定MDR1C3435T遗传多态性和CYP2C19基因型。
    结果:在这项研究中招募的207名儿童中,CYP2C19EM的比值,IM,PM表型为40.1%,46.4%,和16.9%,分别。MDR13435C/C多态性患者占43.0%,MDR13435C/T为40.1%,MDR13435T/T为16.9%。CYP2C19EM基因型患者幽门螺杆菌感染的治愈率为78.3%;IM基因型为83.3%,PM基因型为96,4%(p=0.07)。根除幽门螺杆菌的成功率为85.4%,86.7%,MDR13435C/C的患者为68.6%,C/T,和T/T,分别(p=0.02)。多因素logistic回归分析发现MDR1C3435T基因多态性是患者治疗失败的独立危险因素,CYP2C19基因型不影响幽门螺杆菌根除。
    结论:基于抗生素敏感性和埃索美拉唑的治疗方案根除幽门螺杆菌的率在CYP2C19表型之间无显著差异。MDR1C3435T多态性是影响儿童幽门螺杆菌根除结果的因素之一。
    BACKGROUND: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate.
    METHODS: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger\'s principle.
    RESULTS: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication.
    CONCLUSIONS: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children.
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  • 文章类型: Journal Article
    包括CYP2C19和CYP2D6在内的细胞色素P450酶对于抗抑郁药代谢很重要,并且已经确定了这些基因的多态性以预测代谢物水平。尽管如此,需要更多的证据来了解遗传变异对抗抑郁反应的影响.在这项研究中,我们收集了13项欧洲和东亚血统人群的个体临床和遗传数据.抗抑郁反应在临床上被评估为缓解和百分比改善。估算的基因型用于将遗传多态性翻译为代谢表型(差,中间,正常,和快速超快速)CYP2C19和CYP2D6。CYP2D6结构变异不能从基因型数据中推算,限制代谢表型的确定,并排除与反应相关的测试。使用正常代谢者作为参考检查CYP2C19代谢表型与治疗反应的关联。在5843名抑郁症患者中,与正常代谢者相比,CYP2C19代谢不良者的缓解率在标称意义上较高,但在多次测试校正后未存活(OR=1.46,95%CI[1.03,2.06],p=0.033,异质性I2=0%,亚组差异p=0.72)。没有代谢表型与相对于基线的改善百分比相关。通过主要由CYP2C19代谢的抗抑郁药进行分层后,未发现代谢表型与抗抑郁药反应之间存在关联。代谢表型表现出频率差异,但没有效果,在欧洲和东亚血统研究之间。总之,使用基因型从遗传变异推断的代谢表型与抗抑郁反应无关.CYP2C19代谢不良可能有助于抗抑郁药效,需要更多证据。测序和靶向药物遗传学测试,除了副作用的信息,抗抑郁剂量,抑郁措施,和不同的祖先研究,将更充分地捕获代谢表型的影响。
    Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.
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  • 文章类型: Journal Article
    Clothianidin,被归类为第二代新烟碱,由于其对害虫的高效能,已取得了广泛的应用。这种广谱的使用导致了它在环境调查中的频繁检测。CYP2C19和CYP3A4对于将噻虫胺转化为去甲基-噻虫胺(dm-噻虫胺)至关重要。这些CYP450的表达可能受到遗传多态性的显着影响。我们研究的目的是检查27种CYP3A4变体和31种CYP2C19变体对重组昆虫微粒体中噻虫胺代谢的催化作用。通过完善的孵育程序评估这些变体。此外,其代谢物dm-clothianidin的浓度通过使用超高效液相色谱串联质谱(UPLC-MS/MS)进行定量。最后,这些CYP3A4和CYP2C19变体的动力学参数是通过应用Michaelis-Menten动力学分析拟合数据来计算的.观察到的酶活性变化与噻虫胺向dm-噻虫胺的代谢转化有关。在CYP2C19代谢途径中,一个变体(CYP2C19.23)在内在清除率(CLint)中没有显着变化,四个变体(CYP2C19.29、.30、.31和L16F)显示出Clint的显着增加(110.86-183.46%),剩下的25个变异体显示出相当大的减少(26.38-89.79%),最大降幅为73.62%(CYP2C19.6)。在CYP3A4代谢途径中,26个变体显示出明显减少的CLint(10.54-52.52%),最大降幅为89.46%(CYP3A4.20)。我们的结果表明,CYP3A4和CYP2C19的大多数变体在不同程度上显着改变了与噻虫胺代谢相关的酶活性。这项研究为评估农药的代谢行为提供了新的见解,并提供了可以指导临床解毒策略的关键数据。
    Clothianidin, classified as a second-generation neonicotinoid, has achieved extensive application due to its high efficacy against insect pests. This broad-spectrum usage has resulted in its frequent detection in environmental surveys. CYP2C19 and CYP3A4 are crucial for converting clothianidin to desmethyl-clothianidin (dm-clothianidin). The expression of these CYP450s can be significantly influenced by genetic polymorphisms. The objective of our research was to examine the catalytic effects of 27 CYP3A4 variants and 31 CYP2C19 variants on the metabolism of clothianidin within recombinant insect microsomes. These variants were assessed through a well-established incubation procedure. In addition, the concentration of its metabolite dm-clothianidin was quantified by employing an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Lastly, the kinetic parameters of these CYP3A4 and CYP2C19 variants were calculated by applying Michaelis-Menten kinetic analysis to fit the data. The observed changes in enzyme activity were related to the metabolic transformation of clothianidin to dm-clothianidin. In the CYP2C19 metabolic pathway, one variant (CYP2C19.23) showed no notable change in intrinsic clearance (CLint), four variants (CYP2C19.29, .30, .31 and L16F) demonstrated a marked increase in CLint (110.86-183.46 %), and the remaining 25 variants exhibited a considerable decrease in CLint (26.38-89.79 %), with a maximum decrease of 73.62 % (CYP2C19.6). In the CYP3A4 metabolic pathway, 26 variants demonstrated significantly reduced CLint (10.54-52.52 %), with a maximum decrease of 89.46 % (CYP3A4.20). Our results suggested that most variants of CYP3A4 and CYP2C19 significantly altered the enzymatic activities associated with clothianidin metabolism to various degrees. This study provides new insights into assessing the metabolic behavior of pesticides and delivers crucial data that can guide clinical detoxification strategies.
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  • 文章类型: Journal Article
    阻塞性肥厚型心肌病(oHCM)是HCM的一种亚型,其特征是由心肌肥大和二尖瓣和器官的解剖改变引起的左心室流出道阻塞。Mavacamten,一种心脏肌球蛋白抑制剂,主要由CYP2C19在肝脏中代谢,是第一种也是唯一一种被批准用于治疗有症状的纽约心脏协会(NYHA)II-III类oHCM的靶向药物。以前的药代动力学(PK)的mavacamten的健康白种人的结果,日本人,亚洲参与者证明,mavacamten暴露受CYP2C19代谢状态的影响。这个开放标签,平行组,I期试验旨在确定具有不同CYP2C19基因型的健康中国参与者中mavacampen的PK和安全性。主要结果是确定健康中国参与者中mavacamten的PK;次要结果是检查安全性和耐受性。在禁食的健康成年中国人单次口服15或25毫克mavacamten后,Cmax在0.6-1.5h的中值Tmax内达到,表明吸收迅速。个体差异中等,携带无功能CYP2C19等位基因(*2/*2,*3/*3或*2/*3)的个体表现出更长的半衰期和增加的总暴露量。CYP2C19基因型分层后,与之前的PK研究相比,不同种族群体的mavacamten总暴露量相似.在这项研究中没有观察到显著的不良事件。在所有CYP2C19基因型中,单次口服15mg的mavacamten具有良好的耐受性,25mg剂量在CYP2C19基因型UM/RM/NM的健康参与者中耐受性良好。中国健康人群中mavacampen的PK谱与其他健康人群一致。
    Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6-1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.
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  • 文章类型: Journal Article
    伏立康唑是治疗和预防真菌感染的基石。虽然在预防性治疗期间CYP2C19基因型与伏立康唑暴露之间存在良好的相关性,在侵袭性曲霉病患者中没有发现相关性。促炎细胞因子导致CYP2C19酶活性的抑制(并且可能导致表型转化)。在这里,我们调查了炎症之间的关系,CYP2C19基因型预测表型,和CYP2C19活性的患者接受伏立康唑。数据来自两项研究伏立康唑治疗的前瞻性研究(NCT02074462和NCT00893555)。剂量校正的伏立康唑血浆浓度和C反应蛋白(CRP)被用作CYP2C19活性和炎症的替代因子,分别。经过数据提取和综合,可获得39例患者的配对伏立康唑和CRP测量数据.CYP2C19基因型预测代谢表型的分布为31%中间(IM),41%正常(NM),和28%的快速代谢者(RM)。在炎症期间,剂量校正的伏立康唑水平增加了245%,278%,CYP2C19NMs和RM为486%,分别。具有中等或高CRP水平(>50mg/L)的患者被表型转化为较低代谢表型,而与他们的CYP2C19基因型无关。在对8名患者的亚组分析中,有或没有炎症的纵向数据,剂量校正的伏立康唑和CRP测量的模式相似,随着CRP水平降低或升高,CYP2C19活性降低。总之,伏立康唑的血浆浓度在炎症期间由于CYP2C19活性的下调而增加。虽然CYP2C19RM的这种影响似乎最大,CYP2C19基因型之间未观察到临床相关差异.
    Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.
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  • 文章类型: Journal Article
    背景:尽管抗血小板治疗(APT),接受血运重建的心血管患者仍有发生血栓事件的高风险.个体对APT的反应差异很大,由于治疗中血小板反应性(HTPR)较高,在≤40%的患者中,导致对血栓事件的保护不足。血小板反应的个体差异会损害单个患者水平的APT指导。不幸的是,随着时间的推移,人们对个体血小板对APT的反应知之甚少,准确测量残余血小板反应性的时机,或监测残余血小板反应性的最佳测试。
    目的:研究接受氯吡格雷治疗的颈动脉内膜切除术(CEA)患者随时间的残余血小板反应性变异性。
    方法:在接受CEA的患者中,单中心,使用VerifyNow的观察性研究(ADP诱导的与纤维蛋白原包被的珠子结合的浊度变化),VASP测定(血管扩张剂刺激的磷蛋白磷酸化的定量),和四个围手术期时间点的基于流式细胞术的检测(PACT)。基因分型鉴定了慢代谢物(CYP2C19*2和CYP2C19*3)和快代谢物(CYP2C19*17)。
    结果:在2017年12月至2019年11月之间,纳入了50例接受CEA的患者。用VerifyNow(p=<.001)和VASP(p=.029)测量的血小板反应性随时间变化,而PACT没有。VerifyNow确定了手术后改变HTRP状态的患者。VASP确定了8周后改变HTPR状态的患者(p=.018)。CYP2C19基因分型鉴定出13个慢代谢者。
    结论:在接受CEA的患者中,围手术期血小板反应性测量值随着时间的推移而波动,血小板反应性测定之间几乎不一致.因此,用VerifyNow和VASP测定测量的个体患者的HTPR状态随时间变化。因此,通常使用的围手术期血小板反应性测量对于调整围手术期APT策略似乎不可靠.
    BACKGROUND: Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity.
    OBJECTIVE: To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel.
    METHODS: Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers.
    RESULTS: Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers.
    CONCLUSIONS: In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.
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