Published Online:24 Nov 2005https://doi.org/10.2217/14622416.6.5.503
Abstract
Vitamin K antagonists (coumarins) are widely-used oral anticoagulants for the prevention of venous thromboembolism and strokes. Wide inter-individual variation in dose response and frequent bleeds characterize the initiation of coumarin therapy. Over the past 10 years both genetic and nongenetic determinants of coumarin dose response have been identified. A comprehensive pharmacogenetics approach to warfarin therapy has the potential to improve the safety and efficiency of warfarin initiation.
Bibliography
- 1 Hirsh J, Dalen J, Anderson DR et al.: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest119, 8S–21S (2001).
- 2 Linder MW: Genetic mechanisms for hypersensitivity and resistance to the anticoagulant warfarin. Clin. Chim. Acta308, 9–15 (2001).
- 3 Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD: The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J. Am. Coll. Surg.194, 267–273 (2002).
- 4 Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL: Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb. Haemost.91, 87–94 (2004).
- 5 Beyth R, Milligan PE, Gage BF: Risk factors for bleeding in patients taking coumarins: Curr. Hem. Reports. 1, 41–49 (2002).
- 6 Crowther MA, Ginsberg JB, Kearon C et al.: A randomized trial comparing 5 mg and 10 mg warfarin loading doses: Arch. Intern. Med.159, 46–48 (1999).
- 7 Kovacs MJ, Rodger M, Anderson DR et al.: Comparison of 10 mg and 5 mg warfarin initiation nomograms together with low-molecular-weight heparin for out-patient treatment of acute venous thromboembolism: a randomized, double-blind, controlled trial. Ann. Intern. Med.138, 714–719 (2003).
- 8 Fennerty A, Dolben J, Thomas P et al.: Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br. Med. J. (Clin. Res. Ed.)288, 1268–1270 (1984).
- 9 Voora D, Eby C, Linder MW et al.: Prospective dosing of warfarin based on cytochrome P450 2C9 genotype. Thromb. Haemost.93, 700–705 (2005).• A prospective study of pharmacogenetics-based warfarin therapy.
- 10 Park BK: Warfarin: metabolism and mode of action. Biochem. Pharmacol.37, 19–27 (1988).
- 11 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW: Identification of the gene for vitamin K epoxide reductase. Nature427, 541–544 (2004).•• Describes the identification of VKORC1.
- 12 Rost S, Fregin A, Ivaskevicius V et al.: Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency Type 2. Nature427, 537–541 (2004).•• Describes the identification of VKORC1 and mutations associated with warfarin resistance.
- 13 Miners JO, Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol.45, 525–538 (1998).
- 14 Redman AR: Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy21, 235–242 (2001).
- 15 Takahashi H, Echizen H: Pharmacogenetics of warfarin elimination and its clinical implications. Clin. Pharmacokinet.40, 587–603 (2001).
- 16 Thijssen HH, Flinois J-P, Beaune PH: Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab. Dispos.28, 1284–1290 (2000).
- 17 Thijssen HH, Baars LG, Drittij-Reijnders MJ: Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat. Drug Metab. Dispos.13, 593–597 (1985).
- 18 Takahashi H, Wilkinson GR, Padrini R, Echizen H: CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin. Pharmacol. Ther.75, 376–380 (2004).
- 19 Meinertz T, Kasper W, Kahl C, Jahnchen E: Anticoagulant activity of the enantiomers of acenocoumarol. Br. J. Clin. Pharmacol.5, 187–188 (1978).
- 20 Ufer M, Svensson JO, Krausz KW, Gelboin HV, Rane A, Tybring G: Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur. J. Clin. Pharmacol.60, 173–182 (2004).
- 21 Kirchheiner J, Ufer M, Walter EC et al.: Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics14, 19–26 (2004).
- 22 Fihn SD, Gadisseur AA, Pasterkamp E et al.: Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb. Haemost.90, 260–266 (2003).
- 23 Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H: Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature424, 464–468 (2003).
- 24 Gotoh O: Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J. Biol. Chem.267, 83–90 (1992).
- 25 Lee S, Kim JM, Chung CS, Cho KJ, Kim JH: Polymorphism in CYP2C9 as a non-critical factor of warfarin dosage adjustment in Korean patients. Arch. Pharm. Res.26, 967–972 (2003).
- 26 Takahashi H, Wilkinson GR, Caraco Y et al.: Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Clin. Pharmacol. Ther.73, 253–263 (2003).
- 27 Shintani M, Ieiri I, Inoue K et al: Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: in vitro and in vivo studies. Clin. Pharmacol. Ther.70, 175–182 (2001).
- 28 Takahashi H, Ieiri I, Wilkinson GR et al.: 5′-flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients. Blood103, 3055–3057 (2004).
- 29 Rettie AE, Tai G, Veenstra DL et al.: CYP2C9 exon 4 mutations and warfarin dose phenotype in Asians. Blood101, 2896–2897 (2003).
- 30 Furuya H, Fernandez-Salguero P, Gregory W et al: Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics5, 389–392 (1995).
- 31 Yamazaki H, Inoue K, Chiba K et al.: Comparative studies on the catalytic roles of cytochrome P450 2C9 and its Cys- and Leu-variants in the oxidation of warfarin, flurbiprofen, and diclofenac by human liver microsomes. Biochem. Pharmacol.56, 243–251 (1998).
- 32 Rettie AE, Haining RL, Bajpai M, Levy RH: A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin. Epilepsy Res.35, 253–255 (1999).
- 33 Sullivan-Klose TH, Ghanayem BI, Bell DA et al: The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics6, 341–349 (1996).
- 34 Yamazaki H, Inoue K, Shimada T: Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes. Xenobiotica28, 103–115 (1998).
- 35 Crespi CL, Miller VP: The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics7, 203–210 (1997).
- 36 Henne KR, Gaedigk A, Gupta G, Leeder JS, Rettie AE: Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype. J. Chromatogr. B Biomed. Sci. Appl.710, 143–148 (1998).
- 37 Kaminsky LS, de Morais SM, Faletto MB, Dunbar DA, Goldstein JA: Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol. Pharmacol.43, 234–239 (1993).
- 38 Dickmann LJ, Rettie AE, Kneller MB et al.: Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African–Americans. Mol. Pharmacol.60, 382–387 (2001).
- 39 Lee CR, Goldstein JA, Pieper JA: Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics12, 251–263 (2002).
- 40 Takahashi H, Kashima T, Nomoto S et al.: Comparisons between in vitro and in vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics8, 365–373 (1998).
- 41 Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K: CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics10, 95–104 (2000).
- 42 Steward DJ, Haining RL, Henne KR et al.: Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics7, 361–367 (1997).
- 43 Thijssen HH, Ritzen B: Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin. Pharmacol. Ther.74, 61–68 (2003).
- 44 Imai J, Ieiri I, Mamiya K et al.: Polymorphism of the cytochrome P450 (CYP)2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics10, 85–89 (2000).
- 45 Ieiri I, Tainaka H, Morita T et al.: Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis. Ther. Drug Monit.22, 237–244 (2000).
- 46 Aithal GP, Day CP, Kesteven PJ, Daly AK: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet353, 717–719 (1999).
- 47 Higashi MK, Veenstra DL, Kondo LM et al.: Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA287, 1690–1698 (2002).•• Shows warfarin-related outcomes associated with CYP2C9 variants.
- 48 Hermida J, Zarza J, Alberca I et al.: Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P450 CYP2C9 on sensitivity to acenocoumarol. Blood99, 4237–4239 (2002).
- 49 Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ: Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb. Haemost.91, 1123–1128 (2004).
- 50 Siguret V, Gouin I, Golmard JL, Geoffroy S, Andreux JP, Pautas E: Cytochrome P450 2C9 polymorphisms (CYP2C9) and warfarin maintenance dose in elderly patients. Rev. Med. Interne25, 271–274 (2004).
- 51 Margaglione M, Colaizzo D, D'Andrea G et al.: Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost.84, 775–778 (2000).
- 52 Spreafico M, Peyvandi F, Pizzotti D, Moia M, Mannucci PM: Warfarin and acenocoumarol dose requirements according to CYP2C9 genotyping in North Italian patients. J. Thromb. Haemost.1, 2252–2253 (2003).
- 53 Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R: Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin. Pharmacol. Ther.72, 702–710 (2002).
- 54 Taube J, Halsall D, Baglin T: Influence of cytochrome P450 CYP2C9 polymorphisms on warfarin sensitivity and risk of overanticoagulation in patients on long-term treatment. Blood96, 1816–1819 (2000).
- 55 Tassies D, Freire C, Pijoan J et al.: Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica87, 1185–1191 (2002).
- 56 Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H, Conemans J, Bernsen Mj M, de Boer A: Acenocoumarol stabilization is delayed in CYP2C93 carriers. Clin. Pharmacol. Ther.75, 394–402 (2004).
- 57 Visser LE, van Vliet M, van Schaik RH et al.: The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics14, 27–33 (2004).
- 58 Thijssen HH, Verkooijen IW, Frank HL: The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics10, 757–760 (2000).
- 59 Hummers-Pradier E, Hess S, Adham IM, Papke T, Pieske B, Kochen MM: Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur. J. Clin. Pharmacol.59, 213–219 (2003).
- 60 Palareti G, Leali N, Coccheri S et al.: Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian study on complications of oral anticoagulant therapy. Lancet348, 423–428 (1996).
- 61 Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH: The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann. Intern. Med.124, 970–979 (1996).
- 62 Hylek EM, Singer DE: Risk factors for intracranial hemorrhage in out-patients taking warfarin. Ann. Intern. Med.120, 897–902 (1994).
- 63 Oden A, Fahlen M: Oral anticoagulation and risk of death: a medical record linkage study. BMJ325, 1073–1075 (2002).
- 64 Azar AJ, Cannegieter SC, Deckers JW et al.: Optimal intensity of oral anticoagulant therapy after myocardial infarction. J. Am. Coll. Cardiol.27, 1349–1355 (1996).
- 65 Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJM, Vandenbroucke JP, Briet E: Optimal oral anticoagulant therapy in patients with mechanical heart valves. N. Engl. J. Med.333, 11–7 (1995).
- 66 Hylek EM, Go AS, Chang Y et al.: Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med.349, 1019–1026 (2003).
- 67 Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF: Effect of warfarin nonadherence on control of the international normalized ratio. Am. J. Health Syst. Pharm.61, 1258–1264 (2004).
- 68 Schalekamp T, Oosterhof M, van Meegen E et al.: Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin. Pharmacol. Ther.76, 409–417 (2004).
- 69 Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J: Aging and the anticoagulant response to warfarin therapy. Ann. Intern. Med.116, 901–904 (1992).
- 70 Loebstein R, Yonath H, Peleg D et al.: Interindividual variability in sensitivity to warfarin – nature or nurture? Clin. Pharmacol. Ther. 70, 159–164 (2001).
- 71 Shepherd AM, Hewick DS, Moreland TA, Stevenson IH: Age as a determinant of sensitivity to warfarin. Br. J. Clin. Pharmacol.4, 315–320 (1977).
- 72 Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH: Population pharmacokinetics of racemic warfarin in adult patients. J. Pharmacokinet. Biopharm.13, 213–227 (1985).
- 73 Wynne H, Cope L, Kelly P, Whittingham T, Edwards C, Kamali F: The influence of age, liver size and enantiomer concentrations on warfarin requirements. Br. J. Clin. Pharmacol.40, 203–207 (1995).
- 74 Kamali F, Khan TI, King BP et al.: Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin. Pharmacol. Ther.75, 204–212 (2004).
- 75 Blann A, Hewitt J, Siddiqui F, Bareford D: Racial background is a determinant of average warfarin dose required to maintain the INR between 2.0 and 3.0. Br. J. Haematol.107, 207–209 (1999).
- 76 James AH, Britt RP, Raskino CL, Thompson SG: Factors affecting the maintenance dose of warfarin. J. Clin. Pathol.45, 704–706 (1992).
- 77 Absher RK, Moore ME, Parker MH: Patient-specific factors predictive of warfarin dosage requirements. Ann. Pharmacother.36, 1512–1517 (2002).
- 78 Rieder MJ, Reiner AP, Gage BF et al.: VKORC1 haplotypes predict warfarin dose. N. Engl. J. Med.352, 15–23 (2005).•• VKORC1 haplotype groups A and B explained 21–25% of the variance in warfarin dose.
- 79 Alving BM, Strickler MP, Knight RD, Barr CF, Berenberg JL, Peck CC: Hereditary warfarin resistance. Investigation of a rare phenomenon. Arch. Intern. Med.145, 499–501 (1985).
- 80 Kamali F, Edwards C, Butler TJ, Wynne HA: The contribution of plasma (R)- & (S)-warfarin and vitamin K concentrations to intra-individual variability in anticoagulation. Thromb. Haemost.83, 349–350 (2000).
- 81 Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD: Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb. Haemost.93, 23–26 (2005).
- 82 D'Andrea G, D'Ambrosio RL, Di Perna P et al.: A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood105, 645–649 (2005).• Describes the warfarin dose reductions in carriers of VKORC1 variants.
- 83 Bodin L, Verstuyft C, Tregouet DA et al.: Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood106, 135–140 (2005).
- 84 Wajih N, Sane DC, Hutson SM, Wallin R: The inhibitory effect of calumenin on the vitamin K-dependent γ-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J. Biol. Chem.279, 25276–25283 (2004).
- 85 Wallin R, Hutson SM, Cain D, Sweatt A, Sane DC: A molecular mechanism for genetic warfarin resistance in the rat. Faseb. J.15, 2542–2544 (2001).
- 86 Shikata E, Ieiri I, Ishiguro S et al.: Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and γ-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood103, 2630–2635 (2004).
- 87 D'Ambrosio RL, D'Andrea G, Cappucci F et al: Polymorphisms in factor II and factor VII genes modulate oral anticoagulation with warfarin. Haematologica89, 1510–1516 (2004).
- 88 Chu K, Wu SM, Stanley T, Stafford DW, High KA: A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. J. Clin. Invest.98, 1619–1625 (1996).
- 89 D'Andrea G, D'Ambrosio R L, Di Perna P et al.: A polymorphism in VKORC1 gene is associated with an inter-individual variability in the dose-anticoagulant effect of warfarin. Blood 105(2), 645–649 (2004).
- 90 Francis CW, Berkowitz SD, Comp PC et al.: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N. Engl. J. Med.349, 1703–1712 (2003).
- 91 Francis CW, Davidson BL, Berkowitz SD et al: Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann. Intern. Med.137, 648–655 (2002).
- 92 Inoue K, Yamazaki H, Imiya K, Akasaka S, Guengerich FP, Shimada T: Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4’-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics7, 103–113 (1997).
- 93 Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M: Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br. J. Clin. Pharmacol.52, 447–450 (2001).
- 94 Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F: Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem. Biophys. Res. Commun.254, 628–631 (1999).
- 95 Aynacioglu AS, Brockmoller J, Bauer S et al.: Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br. J. Clin. Pharmacol.48, 409–415 (1999).
- 96 Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA: High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur. J. Clin. Pharmacol.57, 47–49 (2001).
- 97 Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM: CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy. Clin. Pharmacol. Ther.75, 198–203 (2004).
- 98 Nasu K, Kubota T, Ishizaki T: Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics7, 405–409 (1997).
- 99 Takahashi H, Kashima T, Nomizo Y et al.: Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin. Pharmacol. Ther.63, 519–528 (1998).
- 100 Wang SL, Huang J, Lai MD, Tsai JJ: Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics5, 37–42 (1995).
- 101 Yoon YR, Shon JH, Kim MK et al.: Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br. J. Clin. Pharmacol.51, 277–280 (2001).
- 102 Sconce EA, Khan TI, Wynne HA et al.: The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood (2005) (Epub ahead of print).
Website
- 201 http://www.immm.ki.se/CYP alleles The Human CYP Allele Nomenclature Committee website.
