caa a22 4500 606158448 CHVBK 20210128100619.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10557-015-6591-8 doi (NATIONALLICENCE)springer-10.1007/s10557-015-6591-8 Warfarin Metabolites in Patients Following Cardiac Valve Implantation: A Contribution of Clinical and Genetic Factors [Elektronische Daten] [Agata Bryk, Ewa Wypasek, Magdalena Awsiuk, Dorota Maj, Anetta Undas] Introduction: Warfarin, a racemic mixture of S- and R-enantiomers, is the cornerstone of therapy in patients following cardiac valve replacement. S-warfarin is metabolized to 7-S-hydroxywarfarin by the cytochrome P450 isoform 2C9 encoded by CYP2C9 gene. R-warfarin is metabolized by multiple cytochromes P450. We sought to assess the impact of clinical and genetic factors on circulating warfarin metabolites following valve implantation. Material and Methods: Venous blood was collected from 120 patients after 3months since elective mitral and/or aortic valve replacement. Plasma S-warfarin, R-warfarin, S-7-hydroxywarfarin, and R-7-hydroxywarfarin were determined using high-performance liquid chromatography. The S-7-hydroxywarfarin/S-warfarin and S-warfarin/R-warfarin (S/R) ratios, along with warfarin sensitivity index (WSI), defined as INR/S-warfarin ratio, were calculated. Vitamin K epoxide reductase complex subunit 1 (VKORC1) c.-1639A, CYP2C9*3 and CYP2C9*2 alleles were determined using real-time polymerase chain reaction. Results: The S-warfarin was higher in former smokers (p = 0.047) and the VKORC1 c.-1639A allele carriers (p < 0.0001). The S-7-hydroxywarfarin was lower in carriers of the VKORC1 c.-1639A allele (p = 0.0005) and CYP2C9*3 (p = 0.047). The S-7-hydroxywarfarin/S-warfarin ratio was lower in the carriers of CYP2C9*3 (p = 0.008), but not in those with VKORC1 -c.1639A allele. The S/R ratio was higher in patients with hypertension (p = 0.01). The independent predictors of elevated S/R ratio defined as the upper quartile were diabetes (p = 0.045), CYP2C9*3 (p < 0.0001) and CYP2C9*2 (p = 0.0002). The independent predictors of elevated WSI were current smoking (p = 0.049), implantation of mechanical valve (p = 0.006) and VKORC1c.-1639A allele (p = 0.007). Conclusion: We conclude that not only genetic, but also several clinical factors affect warfarin metabolites in patients following cardiac valve implantation. Springer Science+Business Media New York, 2015 Warfarin nationallicence Valve implantation nationallicence VKORC1 nationallicence CYP2C9 nationallicence ALT : Alanine aminotransferase nationallicence BMI : Body mass index nationallicence CABG : Coronary artery bypass graft nationallicence CAD : Coronary artery disease nationallicence CI : Confidence interval nationallicence CKD-EPI : Chronic kidney disease epidemiology collaboration nationallicence CV : Coefficients of variability nationallicence CYP2C9 : Cytochrome P450 isoform 2C9 gene nationallicence eGFR : Estimated glomerular filtration rate nationallicence HPLC-UV : High performance liquid chromatography with ultraviolet detection nationallicence INR : International normalized ratio nationallicence SNP : Single nucleotide polymorphism nationallicence S/R ratio : S-warfarin/R-warfarin ratio nationallicence TTR : Time in therapeutic range nationallicence Vd : Volume of distribution nationallicence VKORC1 : Vitamin K epoxide reductase complex subunit 1 gene nationallicence WSI : Warfarin sensitivity index nationallicence Bryk Agata Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut Wypasek Ewa Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut Awsiuk Magdalena John Paul II Hospital, Krakow, Poland aut Maj Dorota Department of Genetics and Animal Breeding, Agriculture University of Krakow, Krakow, Poland aut Undas Anetta Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/3(2015-06-01), 257-264 0920-3206 29:3<257 2015 29 10557 https://doi.org/10.1007/s10557-015-6591-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10557-015-6591-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bryk Agata Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut NATIONALLICENCE 700 1- Wypasek Ewa Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut NATIONALLICENCE 700 1- Awsiuk Magdalena John Paul II Hospital, Krakow, Poland aut NATIONALLICENCE 700 1- Maj Dorota Department of Genetics and Animal Breeding, Agriculture University of Krakow, Krakow, Poland aut NATIONALLICENCE 700 1- Undas Anetta Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/3(2015-06-01), 257-264 0920-3206 29:3<257 2015 29 10557