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Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients

Pouncey, Dakota L.a,b; Hartman, Jessica H.b; Moore, Page C.c; Dillinger, David J.d; Dickerson, Kimberly W.d; Sappington, Daniel R.e; Smith, Eugene S. 3rdf; Boysen, Gunnare; Miller, Grover P.b

Blood Coagulation & Fibrinolysis: November 2018 - Volume 29 - Issue 7 - p 602–612
doi: 10.1097/MBC.0000000000000752
ORIGINAL ARTICLES

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.

aDepartment of Chemistry, Hendrix College, Conway, Arkansas, USA

bDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

cDepartment of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

dDepartment of Pharmacy, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA

eDepartment of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

fDepartment of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA

Correspondence to Grover P. Miller, PhD, Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 516, Little Rock, AR 72205, USA. Tel: +1 501 526 6486; fax: +1 501 686 8169; e-mail: MillerGroverP@uams.edu

Received 12 February, 2018

Revised 24 May, 2018

Accepted 14 June, 2018

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