Pharmacogenetics of Oral Anticoagulants

  • Enrique Jiménez-Varo
  • Marisa Cañadas-Garre
  • Margarita Aguilera
  • Desiree Gonzalez Callejas
  • Cristina Perez Ramirez
  • Miguel A. Calleja Hernández


Coumarin derivates have been considered an ideal target of personalized medicine because of their pharmacological characteristics as vitamin K antagonists. Thus, many pharmacogenetic investigators have focused in this field, developing numerous warfarin algorithms based on CYP2C9 and VKORC1 genotypes. These pharmacogenetic algorithms include both genetic and nongenetic factors.

Coumarin derivates (warfarin in the UK and USA, acenocoumarol and phenprocoumon in European countries) are the most prescribed oral anticoagulants in the prevention and treatment of thromboembolic events associated with atrial fibrillation, prosthetic valves, venous thromboembolism, and orthopedic surgery.

Vitamin K antagonists have demonstrated efficacy in anticoagulation although they have a narrow therapeutic window. Patients need frequent monitoring by measuring the prothrombin time. The main challenge for physicians is to introduce patients as soon as possible within the therapeutic range (INR 2–3) in the beginning of therapy as the risk of undercoagulation, INR <2 (risk of thrombus), or overanticoagulation, INR> 4 (risk of bleeding), is higher in this period.

The adjustment of the dose to achieve effective and stable anticoagulation depends on several environmental factors including age, gender, weight, concomitant medications and interactions with foods containing vitamin K, smoking status and alcohol intake, and genetic factors.

Allelic variants in CYP2C9*2 (Arg144Cys, rs1799853), CYP2C9*3 Ile359Leu (rs1057910), and VKORC1 (rs9923231, rs9934438) gene polymorphisms have demonstrated an influence of about 40 % on coumarin-required dose.

Despite of knowledge that pharmacogenetic models can improve dosing recommendations according to CYP2C9 and VKORC1 polymorphisms and thus would decrease the risk of thrombus and bleeding events during initial phases of anticoagulation, the translation of pharmacogenetic algorithms into clinical practice is a challenge to pursue in the advancement of personalized medicine.

On the other hand, a new wave of oral anticoagulants has been developed to improve the efficiency and safety of anticoagulant therapy and avoid the several drawbacks of vitamin K antagonists. This new generation of anticoagulants is expected to be the alternative in prevention of stroke and systemic embolism in non-valvular atrial fibrillation patients.

In this chapter, we will review the most relevant pharmacogenetic studies performed with coumarin derivates, the application of pharmacogenetics in predicting the optimal coumarin derivates’ initial dose based on genetic and environmental factors, genetic tests available for determination of main gene polymorphisms associated to warfarin sensitivity, the development of new oral anticoagulants (dabigatran, rivaroxaban, apixaban), and comparison of different pharmacological therapies available to use in patients with non-valvular atrial fibrillation requiring long-term anticoagulation.


International Normalize Ratio Oral Anticoagulant Warfarin Dose Dabigatran Etexilate Systemic Embolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717–719PubMedGoogle Scholar
  2. Alberio L (2003) Oral anticoagulation with vitamin K antagonists. Ther Umsch 60:5–9PubMedGoogle Scholar
  3. Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Mansfield JW, Robinson M, Barton S, Brunisholz K, Mower CP, Huntinghouse JA, Rollo JS, Siler D, Bair TL, Knight S, Muhlestein JB, Carlquist JF (2012) A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 125:1997–2005PubMedGoogle Scholar
  4. Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D, Gaston KL, Waddell CD, Chirico MJ, Johnson JA (2006) Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 79:291–302PubMedGoogle Scholar
  5. Babic N, Haverfield EV, Burrus JA, Lozada A, Das S, Yeo KT (2009) Comparison of performance of three commercial platforms for warfarin sensitivity genotyping. Clin Chim Acta 406:143–147PubMedGoogle Scholar
  6. Baetz BE, Spinler SA (2008) Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy 28:1354–1373PubMedGoogle Scholar
  7. Banerjee A, Marín F, Lip GY (2011) A new landscape for stroke prevention in atrial fibrillation: focus on new anticoagulants, antiarrhythmic drugs, and devices. Stroke 42(11):3316–3322PubMedGoogle Scholar
  8. Bazan NS, Sabry NA, Rizk A, Mokhtar S, Badary O (2012) Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients. Int J Clin Pharm 34(6):837–844PubMedGoogle Scholar
  9. Becquemont L (2008) Evidence for a pharmacogenetic adapted dose of oral anticoagulant in routine medical practice. Eur J Clin Pharmacol 64:953–960PubMedGoogle Scholar
  10. Beinema M, Brouwers JR, Schalekamp T, Wilffert B (2008) Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 100(6):1052–1057. ReviewGoogle Scholar
  11. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106(1):135–140PubMedGoogle Scholar
  12. Borgiani P, Ciccacci C, Forte V, Romano S, Federici G, Novelli G (2007) Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics 8:1545–1550PubMedGoogle Scholar
  13. Borobia AM, Lubomirov R, Ramírez E, Lorenzo A, Campos A, Muñoz-Romo R, Fernández-Capitán C, Frías J, Carcas AJ (2012) An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in spanish patients with thromboembolic disease. PLoS One 7:e41360PubMedCentralPubMedGoogle Scholar
  14. Brighton T (2010) Experimental and clinical pharmacology new oral anticoagulant drugs– mechanisms of action. Aust Prescr 33:38–41Google Scholar
  15. Cadamuro J, Dieplinger B, Felder T, Kedenko I, Mueller T, Haltmayer M, Patsch W, Oberkofler H (2010) Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. Eur J Clin Pharmacol 66(3):253–260PubMedGoogle Scholar
  16. Cain D, Hutson SM, Wallin R (1997) Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem 272:29068–29075PubMedGoogle Scholar
  17. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, Hubbard J, Turpaz Y, Langaee TY, Eby C, King CR, Brower A, Schmelzer JR, Glurich I, Vidaillet HJ, Yale SH, Qi Zhang K, Berg RL, Burmester JK (2008) CYP4F2 genetic variant alters required warfarin dose. Blood 111:4106–4112PubMedCentralPubMedGoogle Scholar
  18. Camm AJ et al (2010) Guías de práctica clínica para el manejo de la fibrilación auricular. Rev Esp Cardiol 63(12):1483.e1–1483.e83Google Scholar
  19. Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, Clarke JL, James BC, Anderson JL (2006) Genotypes of the Cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 22:191–197Google Scholar
  20. Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA, Viana MA, Patel SR, Johnson JA (2010) Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 87:459–464PubMedGoogle Scholar
  21. Choonara IA, Haynes BP, Cholerton S, Breckenridge AM, Park BK (1986) Enantiomers of warfarin and vitamin K1 metabolism. Br J Clin Pharmacol 22:729–732PubMedCentralPubMedGoogle Scholar
  22. Cini M, Legnani C, Cosmi B, Guazzaloca G, Valdrè L, Frascaro M, Palareti G (2012) A new warfarin dosing algorithm including VKORC1 3730 G>A polymorphism: comparison with results obtained by other published algorithms. Eur J Clin Pharmacol 68:1167–1174PubMedGoogle Scholar
  23. Colwell CW Jr, Berkowitz SD, Lieberman JR, Comp PC, Ginsberg JS, Paiement G, McElhattan J, Roth AW, Francis CW, EXULT B Study Group (2005) Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 87:2169–2177PubMedGoogle Scholar
  24. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, RE-LY Steering Committee and Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151PubMedGoogle Scholar
  25. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, LawrenceJ LG, Afzal R, Yusuf S, AVERROES Steering Committee and Investigators (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364:806–817PubMedGoogle Scholar
  26. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649PubMedGoogle Scholar
  27. D’Andrea G, D’Ambrosio R, Margaglione M (2008) Oral anticoagulants: pharmacogenetics relationship between genetic and non-genetic factors. Blood Rev 22:127–140PubMedGoogle Scholar
  28. Dahl OE (2012) New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders. Vasc Health Risk Manag 8:45–57PubMedCentralPubMedGoogle Scholar
  29. Daly AK, King BP (2003) Pharmacogenetics of oral anticoagulants. Pharmacogenetics 13:247–252PubMedGoogle Scholar
  30. Davidson T, Husberg M, Janzon M, Oldgren J, Levin LÅ (2013) Cost-effectiveness of dabigatran compared with warfarin for patients with atrial fibrillation in Sweden. Eur Heart J 34(3):177–183PubMedGoogle Scholar
  31. Davis EM, Packard KA, Knezevich JT, Campbell JA (2011) New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome. Pharmacotherapy 31(10):975–1016PubMedGoogle Scholar
  32. Deedwania P, Huang GW (2012) An evidence-based review of apixaban and its potential in the prevention of stroke in patients with atrial fibrillation. Core Evid 7:49–59PubMedCentralPubMedGoogle Scholar
  33. Dezee KJ, Shimeall WT, Douglas KM, Shumway NM, O’malley PG (2006) Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med 166(4):391–397PubMedGoogle Scholar
  34. Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, O’Donnell M, Hohnloser SH, Hankey GJ, Shestakovska O, Yusuf S, AVERROES Steering Committee and Investigators (2012) Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 1:225–231Google Scholar
  35. Douketis JD (2011) Dabigatran as anticoagulant therapy for atrial fibrillation. Which patients should receive it, which patients may not need it, and other practical aspects of patient management. Pol Arch Med Wewn 121(3):73–80PubMedGoogle Scholar
  36. DrugBank (2012a) Rivaroxaban Accessed 7 May 2012
  37. DrugBank (2012b) Acenocoumarol (DB01418). Accessed 7 May 2012
  38. Duran Parrondo C et al (2003) Anticoagulación oral. An Med Interna 20:377–384PubMedGoogle Scholar
  39. Eckman MH, Rosand J, Greenberg SM, Gage BF (2009) Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 150:73–83PubMedGoogle Scholar
  40. Eikelboom JW, O’Donnell M, Yusuf S, Diaz R, Flaker G, Hart R, Hohnloser S, Joyner C, Lawrence J, Pais P, Pogue J, Synhorst D, Connolly SJ (2010) Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 159:348–353PubMedGoogle Scholar
  41. Eitz T et al (2008) International normalized ratio self-management lowers the risk of thromboembolic events after prosthetic heart valve replacement. Ann Thorac Surg 85:949–955PubMedGoogle Scholar
  42. Epstein RS, Moyer TP, Aubert RE, O’Kane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR (2010) Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin effectiveness study). J Am Coll Cardiol 55:2804–2812PubMedGoogle Scholar
  43. Eriksson BI, Quinlan DJ, Weitz JI (2009) Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet 48:1–22PubMedGoogle Scholar
  44. European Medicine Agency (2012a) EPAR summary for the public. EMA/240842/2011 EMEA/H/C/48. Accessed 10 Sept 2012
  45. European Medicine Agency (2012b) Summary of Rivaroxaban characteristics. Accessed 10 Sept 2012
  46. European Medicines Agency (2012c) Updates on safety of Pradaxa Accessed 10 Sept 2012
  47. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491PubMedGoogle Scholar
  48. FDA News and Events (2012b) FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm. Accessed 7 May 2012
  49. FDA News and Events (2012c) NEWS RELEASE. FDA clears genetic lab test for Warfarin sensitivity. Accessed 10 Sept 2012
  50. Fava C, Montagnana M, Almgren P, Rosberg L, Lippi G, Hedblad B, Engström G, Berglund G, Minuz P, Melander O (2008) The V433M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure. Hypertension 52:373–380PubMedGoogle Scholar
  51. FDA. U.S. Food and Drug Administration (2012a) COUMADIN® TABLETS (Warfarin sodium Tablets, USP) Crystalline COUMADIN® FOR INJECTION (Warfarin Sodium for Injection, USP). Accessed 7 May 2012
  52. FDA. U.S. Food and Drug Administration (2012b) XARELTO (rivaroxaban) tablets, for oral use. Accessed 7 May 2012
  53. Francis CW (2008) New issues in oral anticoagulants. Hematol Am Soc Hematol Educ Program 2008(1):259–265. doi: 10.1182/asheducation-2008.1.259 Google Scholar
  54. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr, EXULT A Study Group (2003) Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 349:1703–1712PubMedGoogle Scholar
  55. Fu Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Shindo A, Ohta M, Soma M, Aoi N, Sato M, Ozawa Y, Ma Y, Matsumoto K, Doba N, Hinohara S (2009) A haplotype of the CYP4F2 gene associated with myocardial infarction in Japanese men. Mol Genet Metab 96:145–147PubMedGoogle Scholar
  56. Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D, American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, Interdisciplinary Council on Quality of Care and Outcomes Research (2011) Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42(1):227–276PubMedGoogle Scholar
  57. Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL (2004) Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 91:87–94PubMedGoogle Scholar
  58. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 84:326–331PubMedCentralPubMedGoogle Scholar
  59. Geisen C, Watzka M, Sittinger K et al (2005) VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 94:773–779PubMedGoogle Scholar
  60. Giorgi MA, Miguel LS (2012) Rivaroxaban in atrial fibrillation. Vasc Health Risk Manag 8:525–531PubMedCentralPubMedGoogle Scholar
  61. González-Juanatey JR, Alvarez-Sabin J, Lobos JM, Martínez-Rubio A, Reverter JC, Oyagüez I, González-Rojas N, Becerra V (2012) Cost-effectiveness of Dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. Rev Esp Cardiol 65(10):901–910PubMedGoogle Scholar
  62. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, ARISTOTLE Committees and Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992PubMedGoogle Scholar
  63. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE (1996) Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 333:447–458PubMedGoogle Scholar
  64. Hirsh J (1992) Antithrombotic therapy in deep vein thrombosis and pulmonary embolism. Am Heart J 123(4 Pt 2):1115–1122PubMedGoogle Scholar
  65. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D (2001) Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119(1 Suppl):8S–21SPubMedGoogle Scholar
  66. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE (2003) Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 349:1019–1026PubMedGoogle Scholar
  67. Infiniti Warfarin Assay (2012) Available from: Accessed 10 Sept 2012
  68. International Warfarin Pharmacogenetics Consortium (IWPC) Algorithm (2012) Available from: Accessed 7 May 2012
  69. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764PubMedGoogle Scholar
  70. Jähnchen E, Meinertz T, Gilfrich HJ, Groth U, Martini A (1976) The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther 20:342–349PubMedGoogle Scholar
  71. Johnson EG, Horne BD, Carlquist JF, Anderson JL (2011) Genotype-based dosing algorithms for warfarin therapy: data review and recommendations. Mol Diagn Ther 15:255–264PubMedGoogle Scholar
  72. Jonas DE, McLeod HL (2009) Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 30:375–386PubMedGoogle Scholar
  73. Kamali F, Pirmohamed M (2006) The future prospects of pharmacogenetics in oral anticoagulation therapy. Br J Clin Pharmacol 61(6):746–751PubMedCentralPubMedGoogle Scholar
  74. King CR, Porche-Sorbet RM, Gage BF, Ridker PM, Renaud Y, Phillips MS, Eby C (2008) Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J Clin Pathol 129:876–883PubMedGoogle Scholar
  75. King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, Porche-Sorbet RM, Ridker PM, Gage BF (2010) Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost 104:750–754PubMedCentralPubMedGoogle Scholar
  76. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61(12):873–880PubMedGoogle Scholar
  77. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2006) Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59–7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 46:549–558PubMedGoogle Scholar
  78. Kubitza D, Becka M, Roth A, Mueck W (2008) Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 24:2757–2765PubMedGoogle Scholar
  79. Langley MR, Booker JK, Evans JP, McLeod HL, Weck KE (2009) Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms. J Mol Diagn 11:216–225PubMedCentralPubMedGoogle Scholar
  80. Lefferts JA, Schwab MC, Dandamudi UB, Lee HK, Lewis LD, Tsongalis GJ (2010) Warfarin genotyping using three different platforms. Am J Transl Res 2:441–446PubMedCentralPubMedGoogle Scholar
  81. Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF (2010) Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther 87:572–578PubMedCentralPubMedGoogle Scholar
  82. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544PubMedGoogle Scholar
  83. Li C, Schwarz UI, Ritchie MD, Roden DM, Stein CM, Kurnik D (2009) Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood 113:3925–3930PubMedCentralPubMedGoogle Scholar
  84. Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A (2011) Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 9:2168–2175PubMedGoogle Scholar
  85. Limdi NA, Veenstra DL (2008) Warfarin pharmacogenetics. Pharmacotherapy 28(9):1084–1097PubMedCentralPubMedGoogle Scholar
  86. Limdi NA, Arnett DK, Goldstein JA, Beasley TM, McGwin G, Adler BK, Acton RT (2008) Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenomics 9:511–526PubMedCentralPubMedGoogle Scholar
  87. Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM (2009) Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 43:119–128PubMedCentralPubMedGoogle Scholar
  88. Lip GY, Lane DA (2010) Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med 123:785–789PubMedGoogle Scholar
  89. Lip GY, Huber K, Andreotti F, Arnesen H, Airaksinen KJ, Cuisset T, Kirchhof P, Marín F, European Society of Cardiology Working Group on Thrombosis (2010) Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost 103:13–28PubMedGoogle Scholar
  90. Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, Amariglio N, Cohen Y, Ken-Dror G, Almog S, Gak E (2007) A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 109:2477–2480PubMedGoogle Scholar
  91. López-Parra AM, Borobia AM, Baeza C, Arroyo-Pardo E, Carcas AJ (2013) A multiplex assay to detect variations in the CYP2C9, VKORC1, CYP4F2 and APOE genes involved in acenocoumarol metabolism. Clin Biochem 46(1–2):167–169PubMedGoogle Scholar
  92. Lund K, Gaffney D, Spooner R, Etherington AM, Tansey P, Tait RC (2012) Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates. Br J Haematol 158(2):256–261PubMedGoogle Scholar
  93. Manolopoulos VG, Ragia G, Tavridou A (2010) Pharmacogenetics of coumarinic oral anticoagulants. Pharmacogenomics 4:493–496Google Scholar
  94. Margaglione M, Colaizzo D, D’Andrea G, Brancaccio V, Ciampa A, Grandone E, Di Minno G (2000) Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 84:775–778PubMedGoogle Scholar
  95. Markatos CN, Grouzi E, Politou M, Gialeraki A, Merkouri E, Panagou I, Spiliotopoulou I, Travlou A (2008) VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients. Pharmacogenomics 9:1631–1638PubMedGoogle Scholar
  96. Maurice CB, Barua PK, Simses D, Smith P, Howe JG, Stack G (2010) Comparison of assay systems for warfarin-related CYP2C9 and VKORC1 genotyping. Clin Chim Acta 411:947–954PubMedGoogle Scholar
  97. Millican EA, Lenzini PA, Milligan PE, Grosso L, Eby C, Deych E, Grice G, Clohisy JC, Barrack RL, Burnett RS, Voora D, Gatchel S, Tiemeier A, Gage BF (2007) Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 110:1511–1515PubMedCentralPubMedGoogle Scholar
  98. Mitchell C, Gregersen N, Krause A (2011) Novel CYP2C9 and VKORC1 gene variants associated with warfarin dosage variability in the South African black population. Pharmacogenomics 12:953–963PubMedGoogle Scholar
  99. Momary KM, Shapiro NL, Viana MA, Nutescu EA, Helgason CM, Cavallari LH (2007) Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics 8:1535–1544PubMedGoogle Scholar
  100. National Heart, Lung, and Blood Institute (2012) Clarification of Optimal Anticoagulation Through Genetics (COAG) [ identifier NCT00839657]. US National Institutes of Health, Available from: Accessed 20 Feb 2012
  101. Ngui JS, Chen Q, Shou M, Wang RW, Stearns RA, Baillie TA, Tang W (2001) In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4′- and 10-hydroxywarfarin. Drug Metab Dispos 29:877–886PubMedGoogle Scholar
  102. Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, Hasegawa A, Yamamoto K, Horiuchi R (2006) VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 80:169–178PubMedGoogle Scholar
  103. Osman A, Enström C, Arbring K, Söderkvist P, Lindahl TL (2006) Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost 4:1723–1729PubMedGoogle Scholar
  104. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, Investigators ROCKETAF (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891PubMedGoogle Scholar
  105. Perera MA, Gamazon E, Cavallari LH, Patel SR, Poindexter S, Kittles RA, Nicolae D, Cox NJ (2011) The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin Pharmacol Ther 89:408–415PubMedCentralPubMedGoogle Scholar
  106. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F (2011) The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10(1):61–75PubMedGoogle Scholar
  107. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, Pinto D, Chen S, Bonacorsi S, Wong PC, Zhang D (2009) Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 37:74–81PubMedGoogle Scholar
  108. Reeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, Wang PJ, Turakhia MP (2011) Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 154:1–11Google Scholar
  109. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, Gelboin HV, Gonzalez FJ, Trager WF (1992) Hydroxylation of warfarin by human cDNA-expressed Cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 5:54–59Google Scholar
  110. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4:39–42PubMedGoogle Scholar
  111. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293PubMedGoogle Scholar
  112. Rieder MJ, Reiner AP, Rettie AE (2007) Gamma-glutamyl carboxylase (GGCX) tag SNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost 5:2227–2234PubMedGoogle Scholar
  113. Rosemary J, Adithan C (2007) The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Curr Clin Pharmacol 2:93–109PubMedGoogle Scholar
  114. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541PubMedGoogle Scholar
  115. Sagreiya H, Berube C, Wen A, Ramakrishnan R, Mir A, Hamilton A, Altman RB (2010) Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenet Genomics 20:407–413PubMedGoogle Scholar
  116. Schalekamp T, Brassé BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A (2006) VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 80:13–22PubMedGoogle Scholar
  117. Schelleman H, Chen Z, Kealey C, Whitehead AS, Christie J, Price M, Brensinger CM, Newcomb CW, Thorn CF, Samaha FF, Kimmel SE (2007) Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 81(5):742–747PubMedGoogle Scholar
  118. Schelleman H, Limdi NA, Kimmel SE (2008) Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics. Pharmacogenomics 9(9):1331–1346PubMedGoogle Scholar
  119. Schulman S, Bijsterveld NR (2007) Anticoagulants and their reversal. Transfus Med Rev 21:37–48PubMedGoogle Scholar
  120. Schulman S, Majeed A (2012) The oral thrombin inhibitor dabigatran: strengths and weaknesses. Semin Thromb Hemost 38:7–15PubMedGoogle Scholar
  121. Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H, Investigators THRIVEIII (2003) Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 349(18):1713–1721PubMedGoogle Scholar
  122. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, RE-COVER Study Group (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352PubMedGoogle Scholar
  123. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358:999–1008PubMedGoogle Scholar
  124. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333PubMedGoogle Scholar
  125. Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ (2009) CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics 10:1243–1255PubMedCentralPubMedGoogle Scholar
  126. Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ (2010) Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 11:781–791PubMedCentralPubMedGoogle Scholar
  127. Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, Ali SS, Mohamed ME, Langaee T, Johnson JA (2011) Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics 21:130–135PubMedCentralPubMedGoogle Scholar
  128. Shaw PB, Donovan JL, Tran MT, Lemon SC, Burgwinkle P, Gore J (2010) Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic. J Thromb Thrombolysis 30:220–225PubMedGoogle Scholar
  129. Shirolkar SC, Fiuzat M, Becker RC (2010) Dronedarone and vitamin K antagonists: a review of drug-drug interactions. Am Heart J 160:577–582PubMedGoogle Scholar
  130. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, Nattel S, Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee (2012) Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 28(2):125–136PubMedGoogle Scholar
  131. Spanish Agency of Medicines and Health Products (2012) Criteria and recommendations for the use of the new oral anticoagulants in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Accessed Sept 2012
  132. Spreafico M, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F, Mannucci PM, Peyvandi F (2008) Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics 9:1237–1250PubMedGoogle Scholar
  133. Stafford DW (2005) The vitamin K cycle. J Thromb Haemost 3:1873–1878PubMedGoogle Scholar
  134. Stangier J, Rathgen K, Stähle H, Mazur D (2010) Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49:259–268PubMedGoogle Scholar
  135. Stehle S, Kirchheiner J, Lazar A, Fuhr U (2008) Pharmacogenetics of oral anticoagulants: a basis for dose individualization. Clin Pharmacokinet 47(9):565–594PubMedGoogle Scholar
  136. Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, Pengo V, Barban M, Padrini R, Ieiri I, Otsubo K, Kashima T, Kimura S, Kijima S, Echizen H (2006) Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 16:101–110PubMedGoogle Scholar
  137. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K (2000) CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 10:95–104PubMedGoogle Scholar
  138. Teichert M, Eijgelsheim M, Rivadeneira F, Uitterlinden AG, van Schaik RH, Hofman A, De Smet PA, van Gelder T, Visser LE, Stricker BH (2009) A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 18(19):3758–3768PubMedGoogle Scholar
  139. Teichert M, Eijgelsheim M, Uitterlinden AG, Buhre PN, Hofman A, De Smet PA, Visser LE, Stricker BH (2011a) Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes. Pharmacogenet Genomics 21(1):26–34PubMedGoogle Scholar
  140. Teichert M, van Noord C, Uitterlinden AG, Hofman A, Buhre PN, De Smet PA, Straus S, Stricker BH, Visser LE (2011b) Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Haematol 153:379–385PubMedGoogle Scholar
  141. The Pharmacogenomics Knowledge Base (2012) Acenocoumarol. Available from: Accessed May 2012
  142. Thijssen HH, Flinois JP, Beaune PH (2000) Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 28:1284–1290PubMedGoogle Scholar
  143. Toon S, Heimark LD, Trager WF, O’Reilly RA (1985) Metabolic fate of phenprocoumon in humans. J Pharm Sci 74(10):1037–1040PubMedGoogle Scholar
  144. Uchino K, Hernandez AV (2012) Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 172:397–402PubMedGoogle Scholar
  145. Ufer M (2005) Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 44:1227–1246PubMedGoogle Scholar
  146. Utrecht Institute for Pharmaceutical Sciences (2012). European Pharmacogenetics of Anticoagulant Therapy – Warfarin (EU-PACT) [ identifier NCT01119300]. US National Institutes of Health, Available from: Accessed 20 Feb 2012
  147. van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, Verhoef TI, van Meegen E, Rosendaal FR, der Zee AH M-v, EU-PACT Study Group (2011) Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 32:1909–1917PubMedGoogle Scholar
  148. Veenstra DL, You JH, Rieder MJ, Farin FM, Wilkerson HW, Blough DK, Cheng G, Rettie AE (2005) Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 15:687–691PubMedGoogle Scholar
  149. Verde Z, Ruiz JR, Santiago C, Valle B, Bandrés F, Calvo E, Lucía A, Gómez Gallego F (2010) A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants. PLoS One 5:e11210PubMedCentralPubMedGoogle Scholar
  150. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P (2005) Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5:262–270PubMedGoogle Scholar
  151. Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, Bentley D, McGinnis R, Deloukas P (2007) Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 121(1):23–34PubMedCentralPubMedGoogle Scholar
  152. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P (2009) The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 113:784–792PubMedCentralPubMedGoogle Scholar
  153. Wajih N, Sane DC, Hutson SM, Wallin R (2004) The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J Biol Chem 279:25276–25283PubMedGoogle Scholar
  154. Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadée W (2008) Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 112:1013–1021PubMedCentralPubMedGoogle Scholar
  155. Wartak SA, Bartholomew JR (2011) Dabigatran: will it change clinical practice? Cleve Clin J Med 78(10):657–664PubMedGoogle Scholar
  156. Washington University School of Medicine (2012) Genetics Informatics Trial (GIFT) of warfarin to prevent DVT [ identifier NCT01006733]. US National Institutes of Health, Available from: Accessed 20 Feb 2012
  157. Weitz JI (2010) New oral anticoagulants in development. Thromb Haemost 103:62–70PubMedGoogle Scholar
  158. Wienkers LC, Wurden CJ, Storch E, Kunze KL, Rettie AE, Trager WF (1996) Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 24:610–614PubMedGoogle Scholar
  159. Wittkowsky AK (2010) New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis 29:182–191PubMedGoogle Scholar
  160. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, Halperin JL, Lip GY, American College of Chest Physicians (2012) Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e531S–e575SPubMedCentralPubMedGoogle Scholar
  161. Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751PubMedGoogle Scholar
  162. Zhang Z, Fasco MJ, Huang Z, Guengerich FP, Kaminsky LS (1995) Human Cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 23:1339–1346Google Scholar

Copyright information

© Springer India 2013

Authors and Affiliations

  • Enrique Jiménez-Varo
    • 1
  • Marisa Cañadas-Garre
    • 1
  • Margarita Aguilera
    • 1
    • 2
  • Desiree Gonzalez Callejas
    • 1
  • Cristina Perez Ramirez
    • 1
  • Miguel A. Calleja Hernández
    • 1
  1. 1.Pharmacogenetics Unit, Pharmacy ServiceHospital Universitario Virgen de las NievesGranadaSpain
  2. 2.Instituto de Nutrición y Tecnología de los Alimentos “José Mataix Verdú” de la Universidad de Granada (INYTA); Centro de Investigación Biomédica (CIBM)GranadaSpain

Personalised recommendations