Pouncey Dakota L, Hartman Jessica H, Moore Page C, Dillinger David J, Dickerson Kimberly W, Sappington Daniel R, Smith Eugene S, Boysen Gunnar, Miller Grover P
Department of Chemistry, Hendrix College, Conway, Arkansas, USA.
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Blood Coagul Fibrinolysis. 2018 Nov;29(7):602-612. doi: 10.1097/MBC.0000000000000752.
: 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.
在这项初步研究中，我们利用华法林患者的代谢物模式，更准确地评估药物代谢中临床相关的差异。我们检验了我们的假设，即血浆代谢物水平与临床因素对华法林对映体R-华法林和S-华法林代谢的影响（华法林代谢表型）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检测的患者。我们确定了他们的CYP2C9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物的14种异构体形式。我们使用分析物水平采用三种新型清除率，对影响药物代谢和剂量反应的临床因素进行多元线性回归分析。竞争性清除率与七个临床因素相关，包括生活方式选择（吸烟）、遗传学（CYP2C9和维生素K环氧化物还原酶1）以及药物相互作用（奥美拉唑），以及年龄、体重和恶性肿瘤。显著的竞争性清除率相关性（P = 0.04至<0.001）解释了21 - 95%的变异性。基于相关性的数量和显著性，它们的表现超过了氧化清除率和代谢清除率。竞争性清除率可以准确评估各因素对维持药物药理活性形式及相关代谢物水平与剂量反应的重要性，从而提供一种策略，以尽量减少不良事件并提高抗凝治疗期间的安全性。这种独特的能力可以为未来一项规模更大、患者队列更多的研究提供一种策略，以更准确地评估临床因素对导致华法林剂量反应的活性药物水平的重要性。
