Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients
Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients
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DOI：
10.1097/mbc.0000000000000752
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发表时间：
2018-11-01
影响因子：
1.1
通讯作者：
Miller, Grover P.
中科院分区：
文献类型：
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作者：
Pouncey, Dakota L.;Hartman, Jessica H.;Miller, Grover P.
在这项初步研究中，我们利用华法林患者的代谢模式，以更准确地评估药物代谢的临床相关差异。我们检验了我们的假设，即血浆代谢物水平与临床因素对R-华法林和S-华法林代谢（华法林代谢表型）的影响相关。我们招募了29名接受维持剂量并在目标治疗范围内进行测试的患者。我们确定了他们的CYP 2C 9和维生素K环氧化物还原酶基因型，并分析了华法林及其代谢产物的14种异构体。我们采用了三种新型的清除率，使用分析物水平进行多重线性回归分析，临床因素影响药物代谢和剂量反应。竞争性清除率与7个临床因素相关，包括生活方式选择（吸烟）、遗传学（CYP 2C 9和维生素K环氧化物还原酶1）和药物相互作用（奥美拉唑），以及与年龄、体重和恶性肿瘤的沿着。显著的竞争清除率相关性（P=0.04至< 0.001）解释了21-95%的变异性。根据相关性的数量和意义，它们的性能超过了氧化和代谢清除率。竞争性清除率可以准确评估维持药物和代谢物的非活性形式水平的因素的重要性，从而提供一种策略，以尽量减少不良事件，提高抗凝治疗期间的安全性。这种独特的能力可以为未来更大规模的患者队列研究提供一种策略，以更准确地评估临床因素对华法林剂量反应的影响。版权所有（C）2018威科医疗集团All rights reserved.
For this pilot study, we leveraged metabolite patterns for warfarin patients to more accurately assess clinically relevant differences in drug metabolism. We tested our hypothesis that plasma metabolite levels correlate with the influence of clinical factors on R-warfarin and S-warfarin metabolism (warfarin metabolic phenotype). We recruited 29 patients receiving a maintenance dose and testing within targeted therapeutic range. We determined their CYP2C9 and vitamin K epoxide reductase genotype and profiled 14 isomeric forms of warfarin and its metabolites. We employed three novel types of clearance ratios using analyte levels to perform multiple-linear regression analyses with clinical factors impacting drug metabolism and dose-responses. Competitive clearance ratios correlated with seven clinical factors including lifestyle choices (smoking), genetics (CYP2C9 and vitamin K epoxide reductase 1), and drug interactions (omeprazole) along with age, weight, and malignancy. Significant competitive clearance ratio correlations (P=0.04 to < 0.001) explained 21-95% variability. Their performances surpassed that of oxidative and metabolic clearance ratios based on the number and significance of correlations. Competitive clearance ratios may accurately assess significance of factors on maintaining levels of pharmacologically active forms of the drug and metabolites related to dose-responses and thus provide a strategy to minimize adverse events and improve safety during anticoagulant therapy. This unique capacity could provide a strategy in a future, higher power study with a larger cohort of patients to more accurately assess the significance of clinical factors on active drug levels contributing to warfarin dose-responses. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.