Skip to main content

Comparative Pharmacokinetics of Vitamin K Antagonists

Warfarin, Phenprocoumon and Acenocoumarol

Abstract

Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a race-mate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors.

Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9.

In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

This is a preview of subscription content, access via your institution.

Fig. 1
Table I
Fig. 2
Table II
Fig. 3

References

  1. Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19(1): 97–107

    PubMed  CAS  Article  Google Scholar 

  2. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114 (5 Suppl.): 445–469S

    Article  Google Scholar 

  3. de Boer-van den Berg M, Thijssen HH, Vermeer C. The in vivo effects of acenocoumarol, phenprocoumon and warfarin on vitamin K epoxide reductase and vitamin K-dependent carboxylase in various tissues of the rat. Biochim Biophys Acta 1986; 884(1): 150–7

    PubMed  Article  Google Scholar 

  4. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005 Jan 15; 105(2): 453–63

    PubMed  CAS  Article  Google Scholar 

  5. Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation 2004; 110 (9 Suppl. 1): 119–26

    Google Scholar 

  6. Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119(90010): 108–121S

    Article  Google Scholar 

  7. Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353(9154): 717–9

    PubMed  CAS  Article  Google Scholar 

  8. Verstuyft C, Robert A, Morin S, et al. Genetic and environmental risk factors for oral anticoagulant overdose. Eur J Clin Pharmacol 2003; 58(11): 739–45

    PubMed  CAS  Google Scholar 

  9. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73(1): 67–74

    PubMed  CAS  Article  Google Scholar 

  10. Ufer M, Svensson JO, Krausz KW, et al. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004; 60(3): 173–82

    PubMed  CAS  Article  Google Scholar 

  11. Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28(11): 1284–90

    PubMed  CAS  Google Scholar 

  12. Rettie AE, Korzekwa KR, Kunze KL, et al. 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 1992; 5(1): 54–9

    PubMed  CAS  Article  Google Scholar 

  13. Takahashi H, Wilkinson GR, Padrini R, et al. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004; 75(5): 376–80

    PubMed  CAS  Article  Google Scholar 

  14. Visser LE, van Schaik RH, van Vliet M, et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004; 92(1): 61–6

    PubMed  CAS  Google Scholar 

  15. Visser LE, van Vliet M, van Schaik RH, et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 and CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004; 14: 27–33

    PubMed  CAS  Article  Google Scholar 

  16. Scordo MG, Pengo V, Spina E, et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002; 72(6): 702–10

    PubMed  CAS  Article  Google Scholar 

  17. 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 1998; 63(5): 519–28

    PubMed  CAS  Article  Google Scholar 

  18. Kirchheiner J, Ufer M, Walter EC, et al. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phen-procoumon in healthy volunteers. Pharmacogenetics 2004; 14(1): 19–26

    PubMed  CAS  Article  Google Scholar 

  19. Thijssen HH, Ritzen Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther 2003; 74_(1): 61–8

    Article  CAS  Google Scholar 

  20. Breckenridge A, Orme ML. The plasma half lives and the pharmacological effect of the enantiomers of warfarin in rats. Life Sci II 1972; 11(7): 337–45

    PubMed  CAS  Article  Google Scholar 

  21. Schmidt W, Jahnchen E. Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats. J Pharm Pharmacol 1977; 29(5): 266–71

    PubMed  CAS  Article  Google Scholar 

  22. Meinertz T, Kasper W, Kahl C, et al. Anticoagulant activity of the enantiomers of acenocoumarol. Br J Clin Pharmacol 1978; 5(2): 187–8

    PubMed  CAS  Article  Google Scholar 

  23. Jahnchen E, Meinertz T, Gilfrich HJ, et al. The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther 1976; 20(3): 342–9

    PubMed  CAS  Google Scholar 

  24. Thijssen HH, Baars LG, Vervoort-Peters HT. Vitamin K 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydrox-ycoumarin anticoagulant activity. Br J Pharmacol 1988; 95(3): 675–82

    PubMed  CAS  Article  Google Scholar 

  25. Kollroser M, Schober Determination of coumarin-type anticoagulants in human plasma by HPLC-electrospray ionization tandem mass spectrometry with an ion trap detector. Clin Chem 2002; 48_(1): 84–91

    Google Scholar 

  26. Boppana VK, Schaefer WH, Cyronak MJ. High-performance liquid-chromatographic determination of warfarin enantiomers in plasma with automated on-line sample enrichment. J Bi-ochem Biophys Methods 2002; 54(1–3): 315–26

    CAS  Article  Google Scholar 

  27. Henne KR, Gaedigk A, Gupta G, et al. Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype. J Chromatogr Biomed Sci Appl 1998; 710(1–2): 143–8

    CAS  Article  Google Scholar 

  28. Ring PR, Bostick JM. Validation of a method for the determination of (R)-warfarin and (S)-warfarin in human plasma using LC with UV detection. J Pharm Biomed Anal 2000; 22(3): 573–81

    PubMed  CAS  Article  Google Scholar 

  29. Rentsch KM, Gutteck-Amsler U, Buhrer R, et al. Sensitive stereospecific determination of acenocoumarol and phenprocoumon in plasma by high-performance liquid chromatography. J Chromatogr Biomed Sci Appl 2000; 742(1): 131–42

    CAS  Article  Google Scholar 

  30. Naidong W, Ring PR, Midtlien C, et al. Development and validation of a sensitive and robust LC-tandem MS method for the analysis of warfarin enantiomers in human plasma. J Pharm Biomed Anal 2001; 25(2): 219–26

    PubMed  CAS  Article  Google Scholar 

  31. Kammerer Kahlich R, Ufer M, et al. Determination of (R)-and (S)-phenprocoumon in human plasma by enantioselective liquid chromatography/electrospray ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom 2004; 18(4): 458–64

    Article  CAS  Google Scholar 

  32. Fasco MJ, Piper LJ, Kaminsky LS. Biochemical applications of a quantitative high-pressure liquid chromatographic assay of warfarin and its metabolites. J Chromatogr 1977; 131: 365–73

    PubMed  CAS  Article  Google Scholar 

  33. Banfield C, Rowland M. Stereospecific fluorescence high-performance liquid chromatographic analysis of warfarin and its metabolites in plasma and urine. J Pharm Sci 1984; 73(10): 1392–6

    PubMed  CAS  Article  Google Scholar 

  34. Chan E, McLachlan AJ, Pegg M, et al. Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol 1994; 37(6): 563–9

    PubMed  CAS  Article  Google Scholar 

  35. de Vries JX, Schmitz-Kummer E. Development of a method for the analysis of warfarin and metabolites in plasma and urine. Am Clin Lab 1995; 14(7): 20–1

    PubMed  Google Scholar 

  36. Takahashi H, Kashima T, Kimura S, et al. Determination of unbound warfarin enantiomers in human plasma and 7-hydroxywarfarin in human urine by chiral stationary-phase liquid chromatography with ultraviolet or fluorescence and online circular dichroism detection. J Chromatogr Biomed Sci Appl 1997; 701(1): 71–80

    CAS  Article  Google Scholar 

  37. Spink DC, Aldous KM, Kaminsky LS. Analysis of oxidative warfarin metabolites by thermospray high-performance liquid chromatography/mass spectrometry. Anal Biochem 1989; 177(2): 307–13

    PubMed  CAS  Article  Google Scholar 

  38. Edelbroek PM, van Kempen GM, Hessing TJ, et al. Analysis of phenprocoumon and its hydroxylated and conjugated metabolites in human urine by high-performance liquid chromatography after solid-phase extraction. J Chromatogr 1990; 530(2): 347–58

    PubMed  CAS  Google Scholar 

  39. de Vries JX, Schmitz-Kummer ES. Determination of the coumarin anticoagulant phenprocoumon, and metabolites in human plasma, urine and breast milk by high-performance liquid chromatography after solid-phase extraction. J Chromatogr Biomed Sci Appl 1994; 655: 63–71

    Article  Google Scholar 

  40. de Vries JX, Simon M, Zimmermann R, et al. Identification of phenprocoumon metabolites in human urine by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr 1985; 338(2): 325–34

    PubMed  Google Scholar 

  41. de Vries JX, Zimmermann R, Harenberg J. Phenprocoumon metabolites in human plasma; characterization by HPLC and GC-MS. Eur J Clin Pharmacol 1986; 29(5): 591–4

    PubMed  Article  Google Scholar 

  42. Heimark LD, Trager WF. A stable isotope assay for phenprocoumon and its metabolites. Biomed Mass Spectrom 1985; 12(2): 67–71

    PubMed  CAS  Article  Google Scholar 

  43. Ufer M, Kammerer Kirchheiner J, et al. Determination of phenprocoumon, warfarin and their monohydroxylated metabolites in human plasma and urine by high-performance liquid chromatography-mass spectrometry after solid-phase extraction. J Chromatogr 2004; 809(2): 217–26

    CAS  Article  Google Scholar 

  44. Thijssen HH, Baars LG, Reijnders MJ. Analysis of acenocoumarin and its amino and acetamido metabolites in body fluids by high-performance liquid chromatography. J Chromatogr 1983; 274: 231–8

    PubMed  CAS  Article  Google Scholar 

  45. Thijssen HH, Janssen GM, Baars LG. Lack of effect of Cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol. Eur J Clin Pharmacol 1986; 30(5): 619–23

    PubMed  CAS  Article  Google Scholar 

  46. Thijssen HH, Drittij MJ, Vervoort LM, et al. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 2001; 70(3): 292–8

    PubMed  CAS  Article  Google Scholar 

  47. Haustein KO, Huiler G. Pharmacokinetics of phenprocoumon. Int J Clin Pharmacol Ther 1994; 32(4): 192–7

    PubMed  CAS  Google Scholar 

  48. O’Reilly RA, Aggeler PM, Leong LS. Studies on the coumarin anticoagulant drugs: the pharmacodynamics of warfarin in man. J Clin Invest 1963; 42: 1542–51

    PubMed  Article  Google Scholar 

  49. Dieterle W, Faigle JW, Montigel C, et al. Biotransformation and pharmacokinetics of acenocoumarol (Sintrom) in man. Eur J Clin Pharmacol 1977; 11(5): 367–75

    PubMed  CAS  Article  Google Scholar 

  50. Hewick DS, McEwen J. Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 1973; 25(6): 458–65

    PubMed  CAS  Article  Google Scholar 

  51. de Vries JX, Volker U. Determination of the plasma protein binding of the coumarin anticoagulants phenprocoumon and its metabolites, warfarin and acenocoumarol, by ultrafiltration and high-performance liquid chromatography. J Chromatogr 1990; 529(2): 479–85

    PubMed  Google Scholar 

  52. Haustein KO. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon. Semin Thromb Hemost 1999; 25(1): 5–11

    PubMed  CAS  Article  Google Scholar 

  53. Thijssen HH, Hamulyak K, Willigers H. 4-Hydroxycoumarin oral anticoagulants: pharmacokinetics-response relationship. Thromb Haemost 1988; 60(1): 35–8

    PubMed  CAS  Google Scholar 

  54. Thijssen HH, Verkooijen IW, Frank HL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics 2000; 10(8): 757–60

    PubMed  CAS  Article  Google Scholar 

  55. Petersen D, Bartheis M, Schumann G, et al. Concentrations of phenprocoumon in serum and serum water determined by high-performance liquid chromatography in patients on oral anticoagulant therapy. Haemostasis 1993; 23(2): 83–90

    PubMed  CAS  Google Scholar 

  56. Russmann S, Gohlke-Barwolf C, Jahnchen E, et al. Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery. Eur J Clin Pharmacol 1997; 52(1): 31–5

    PubMed  CAS  Article  Google Scholar 

  57. Trenk D, Althen H, Jahnchen E, et al. Factors responsible for interindividual differences in the dose requirement of phenprocoumon. Eur J Clin Pharmacol 1987; 33(1): 49–54

    PubMed  CAS  Article  Google Scholar 

  58. Barcellona D, Vannini ML, Fenu L, et al. Warfarin or acenocoumarol: which is better in the management of oral anticoagulants?. Thromb Haemost 1998; 80(6): 899–902

    PubMed  CAS  Google Scholar 

  59. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 1979; 4(1): 1–15

    PubMed  CAS  Article  Google Scholar 

  60. Trager WF, Lewis RJ, Garland WA. Mass spectral analysis in the identification of human metabolites of warfarin. J Med Chem 1970; 13(6): 1196–204

    PubMed  CAS  Article  Google Scholar 

  61. Barker WM, Hermodson MA, Link KP. The metabolism of 4-C14-warfarin sodium by the rat. J Pharmacol Exp Ther 1970; 171(2): 307–13

    PubMed  CAS  Google Scholar 

  62. Lewis RJ, Trager WF. Warfarin metabolism in man: identification of metabolites in urine. J Clin Invest 1970; 49(5): 907–13

    PubMed  CAS  Article  Google Scholar 

  63. Lewis RJ, Trager WF. The metabolic fate of warfarin: studies on the metabolites in plasma. Ann N Y Acad Sci 1971; 179: 205–12

    PubMed  CAS  Article  Google Scholar 

  64. Pohl LR, Nelson SD, Garland WA, et al. The rapid identification of a new metabolite of warfarin via a chemical ionization mass spectrometry ion doublet technique. Biomed Mass Spec-trom 1975; 2(1): 23–30

    CAS  Article  Google Scholar 

  65. Fasco MJ, Dymerski PP, Wos JD, et al. A new warfarin metabolite: structure and function. J Med Chem 1978; 21(10): 1054–9

    PubMed  CAS  Article  Google Scholar 

  66. Kaminsky LS, Dunbar DA, Wang PP, et al. Human hepatic cytochrome P-450 composition as probed by in vitro microsomal metabolism of warfarin. Drug Metab Dispos 1984; 12(4): 470–7

    PubMed  CAS  Google Scholar 

  67. Kaminsky LS. Warfarin as a probe of cytochromes P-450 function. Drug Metab Rev 1989; 20(2-4): 479–87

    PubMed  CAS  Article  Google Scholar 

  68. Moreland TA, Hewick DS. Studies on a ketone reductase in human and rat liver and kidney soluble fraction using warfarin as a substrate. Biochem Pharmacol 1975; 24(21): 1953–7

    PubMed  CAS  Article  Google Scholar 

  69. Hermans JJ, Thijssen HH. The in vitro ketone reduction of warfarin and analogues: substrate stereoselectivity, product stereoselectivity and species differences. Biochem Pharmacol 1989; 38(19): 3365–70

    PubMed  CAS  Article  Google Scholar 

  70. Rettie AE, Eddy AC, Heimark LD, et al. Characteristics of warfarin hydroxylation catalyzed by human liver microsomes. Drug Metab Dispos 1989; 17(3): 265–70

    PubMed  CAS  Google Scholar 

  71. Jansing RL, Chao ES, Kaminsky LS. Phase II metabolism of warfarin in primary culture of adult rat hepatocytes. Mol Pharmacol 1992; 41(1): 209–15

    PubMed  CAS  Google Scholar 

  72. Lewis RJ, Trager WF, Chan KK, et al. Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 1974; 53(6): 1607–17

    PubMed  CAS  Article  Google Scholar 

  73. Toon S, Low LK, Gibaldi M, et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986; 39(1): 15–24

    PubMed  CAS  Article  Google Scholar 

  74. Banfield O’Reilly R, Chan E, et al. Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations. Br J Clin Pharmacol 1983; 16(6): 669–75

    Article  Google Scholar 

  75. Fasco MJ, Vatsis KP, Kaminsky LS, et al. Regioselective and stereoselective hydroxylation of R and S warfarin by different forms of purified cytochrome P-450 from rabbit liver. J Biol Chem 1978; 253(21): 7813–20

    PubMed  CAS  Google Scholar 

  76. Fasco MJ, Piper LJ, Kaminsky LS. Binding of R and S warfarin to hepatic microsomal cytochrome P-450. Arch Biochem Bi-ophys 1977; 182(2): 379–89

    CAS  Article  Google Scholar 

  77. Kaminsky LS, Fasco MJ, Guengerich FP. Comparison of different forms of purified cytochrome P-450 from rat liver by immunological inhibition of regio- and stereoselective metabolism of warfarin. J Biol Chem 1980; 255(1): 85–91

    PubMed  CAS  Google Scholar 

  78. Kaminsky LS, Guengerich FP, Dannan GA, et al. Comparisons of warfarin metabolism by liver microsomes of rats treated with a series of polybrominated biphenyl congeners and by the component-purified cytochrome P-450 isozymes. Arch Biochem Biophys 1983; 225(1): 398–404

    PubMed  CAS  Article  Google Scholar 

  79. Porter WR, Wheeler C, Trager WF. Changes in the metabolic profiles of R- and S-warfarin and R- and S-phenprocoumon as a probe to categorize the effect of inducing agents on microsomal hydroxylases. Biochem Pharmacol 1981; 30(22): 3099–104

    PubMed  CAS  Article  Google Scholar 

  80. Newton DJ, Wang RW, Lu AY. Cytochrome P450 inhibitors: evaluation of specificities in the in-vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 1995; 23(1): 154–8

    PubMed  CAS  Google Scholar 

  81. Mancy A, Dijols S, Poli S, et al. Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9. Biochemistry 1996; 35(50): 16205–12

    PubMed  CAS  Article  Google Scholar 

  82. Kaminsky LS, de Morais SM, Faletto MB, et al. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 1993; 43(2): 234–9

    PubMed  CAS  Google Scholar 

  83. Zhang Z, Fasco MJ, Huang Z, et al. Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 1995; 23(12): 1339–46

    PubMed  CAS  Google Scholar 

  84. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Biochem Pharmacol 1997; 54(11): 1195–203

    PubMed  CAS  Article  Google Scholar 

  85. Wienkers LC, Wurden CJ, Storch E, et al. Formation of (R)-8-hydroxywarfarin in human liver microsomes: a new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 1996; 24(5): 610–4

    PubMed  CAS  Google Scholar 

  86. Toon S, Heimark LD, Trager WF, et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985; 74(10): 1037–40

    PubMed  CAS  Article  Google Scholar 

  87. He M, Korzekwa KR, Jones JP, et al. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys 1999; 372(1): 16–28

    PubMed  CAS  Article  Google Scholar 

  88. Heni N, Glogner P. Pharmacokinetics of phenprocoumon in man investigated using a gas chromatographic method of drug analysis. Naunyn Schmiedebergs Arch Pharmacol 1976; 293(2): 183–6

    PubMed  CAS  Article  Google Scholar 

  89. de Vries JX, Raedsch R, Volker U, et al. Biliary excretion of phenprocoumon and metabolites. Eur J Clin Pharmacol 1988; 35(4): 433–6

    PubMed  Article  Google Scholar 

  90. Heimark LD, Toon S, Gibaldi M, et al. The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans. Clin Pharmacol Ther 1987; 42(3): 312–9

    PubMed  CAS  Article  Google Scholar 

  91. Pohl LR, Haddock RE, Trager WF. Biotransformation of phenprocoumon in the rat. J Med Chem 1975; 18(5): 519–23

    PubMed  CAS  Article  Google Scholar 

  92. Hermans JJ, Thijssen HH. Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4′-nitrowarfarin (acenocoumarol). Xenobiotica 1991; 21(3): 295–307

    PubMed  CAS  Article  Google Scholar 

  93. Hermans JJ, Thijssen HH. Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics. Br J Pharmacol 1993; 110(1): 482–90

    PubMed  CAS  Article  Google Scholar 

  94. Thijssen HH, Baars LG, Hazen MJ, et al. The role of the intestinal microflora in the reductive metabolism of acenocoumarol in man. Br J Clin Pharmacol 1984; 18(2): 247–9

    PubMed  CAS  Article  Google Scholar 

  95. Thijssen HH, Baars LG. The biliary excretion of acenocoumarol in the rat: stereochemical aspects. J Pharm Pharmacol 1987; 39(8): 655–7

    PubMed  CAS  Article  Google Scholar 

  96. Blatrix C, Charonnat S, Tillement JP, et al. Metabolism of a derivative of 4-hydroxy-coumarin: 3 (alfa-acetonyl-p-nitrobenzyl)4-hydroxy-coumarin (Sintrom) in man [in French]. Rev Fr Etud Clin Biol 1968; 13(10): 984–95

    PubMed  CAS  Google Scholar 

  97. Thijssen HH, Baars LG, Reijnders MJ. Acenocoumarol and its amino and acetamido metabolites: comparative pharmacokinetics and pharmacodynamics in the rat. J Pharm Pharmacol 1983; 35(12): 793–8

    PubMed  CAS  Article  Google Scholar 

  98. Thijssen HH, Baars LG. Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?. Br J Clin Pharmacol 1983; 16(5): 491–6

    PubMed  CAS  Article  Google Scholar 

  99. Godbillon J, Richard J, Gerardin A, et al. Pharmacokinetics of the enantiomers of acenocoumarol in man. Br J Clin Pharmacol 1981; 12(5): 621–9

    PubMed  CAS  Article  Google Scholar 

  100. Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics 2003; 13(5): 247–52

    PubMed  CAS  Article  Google Scholar 

  101. Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40(8): 587–603

    PubMed  CAS  Article  Google Scholar 

  102. Rettie AE, Wienkers LC, Gonzalez FJ, et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4(1): 39–42

    PubMed  CAS  Article  Google Scholar 

  103. Haining RL, Hunter AP, Veronese ME, et al. 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 1996; 333(2): 447–58

    PubMed  CAS  Article  Google Scholar 

  104. Yasar U, Eliasson E, Dahl ML, et al. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254(3): 628–31

    PubMed  CAS  Article  Google Scholar 

  105. Stubbins MJ, Harries LW, Smith G, et al. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6(5): 429–39

    PubMed  CAS  Article  Google Scholar 

  106. 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. Pharmacogenetics 1995; 5(6): 389–92

    PubMed  CAS  Article  Google Scholar 

  107. Steward DJ, Haining RL, Henne KR, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 7(5): 361–7

    PubMed  CAS  Article  Google Scholar 

  108. 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. Pharmacogenetics 1998; 8(5): 365–73

    PubMed  CAS  Article  Google Scholar 

  109. Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96(5): 1816–9

    PubMed  CAS  Google Scholar 

  110. Hermida J, Zarza J, Alberca I, et al. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 2002; 99(11): 4237–9

    PubMed  CAS  Article  Google Scholar 

  111. Tassies D, Freire C, Pijoan J, et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002; 87(11): 1185–91

    PubMed  CAS  Google Scholar 

  112. Spreafico M, Peyvandi F, Pizzotti D, et al. Warfarin and acenocoumarol dose requirements according to CYP2C9 genotyping in North-Italian patients. J Thromb Haemost 2003; 1(10): 2252–3

    PubMed  CAS  Article  Google Scholar 

  113. Morin S, Bodin L, Loriot MA, et al. Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther 2004; 75(5): 403–14

    PubMed  CAS  Article  Google Scholar 

  114. Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H, et al. Acenocoumarol stabilization is delayed in CYP2C93 carriers. Clin Pharmacol Ther 2004; 75(5): 394–402

    PubMed  CAS  Article  Google Scholar 

  115. Verstuyft C, Morin S, Robert A, et al. Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers. Pharmacogenetics 2001; 11(8): 735–7

    PubMed  CAS  Article  Google Scholar 

  116. Andre-Kerneis E, Leroy-Matheron C, Gouault-Heilmann M. Early overanticoagulation with acenocoumarol due to a genetic polymorphism of cytochrome P450 CYP2C9. Blood Coagul Fibrinolysis 2003; 14(8): 761–4

    PubMed  Article  Google Scholar 

  117. Zarza J. Major bleeding during combined treatment with indomethacin and low doses of acenocoumarol in a homozygous patient for 2C9*3 variant of cytochrome P-450 CYP2C9. Thromb Haemost 2003; 90(1): 161–2

    PubMed  Google Scholar 

  118. Mannucci PM. Genetic control of anticoagulation. Lancet 1999; 353(9154): 688–9

    PubMed  CAS  Article  Google Scholar 

  119. Pattacini C, Manotti C, Pini M, et al. A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol). Thromb Haemost 1994; 71(2): 188–91

    PubMed  CAS  Google Scholar 

  120. Fihn SD, Gadisseur AA, Pasterkamp E, et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90(2): 260–6

    PubMed  CAS  Google Scholar 

  121. Gadisseur AP, van der Meer FJ, Adriaansen HJ, et al. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002; 117(4): 940–6

    PubMed  CAS  Article  Google Scholar 

  122. Penning-van Beest FJ, Rosendaal FR, Grobbee DE, et al. Course of the international normalized ratio in response to oral vitamin K1 in patients overanticoagulated with phenprocoumon. Br J Haematol 1999; 104(2): 241–5

    PubMed  CAS  Article  Google Scholar 

  123. Ufer M, Kammerer Kahlich R, et al. Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo. Xenobiotica 2004; 34(9): 847–59

    PubMed  CAS  Article  Google Scholar 

  124. Hummers-Pradier E, Hess S, Adham IM, et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 2003; 59(3): 213–9

    PubMed  CAS  Article  Google Scholar 

  125. Schalekamp T, Oosterhof M, van Meegen E, et al. Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2004; 76(5): 409–17

    PubMed  CAS  Article  Google Scholar 

  126. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287(13): 1690–8

    PubMed  CAS  Article  Google Scholar 

  127. Harder S, Thurmann P. Clinically important drug interactions with anticoagulants: an update. Clin Pharmacokinet 1996; 30(6): 416–44

    PubMed  CAS  Article  Google Scholar 

  128. Freedman MD, Olatidoye AG. Clinically significant drag interactions with the oral anticoagulants. Drag Saf 1994; 10(5): 381–94

    CAS  Article  Google Scholar 

  129. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drags and food. Ann Intern Med 1994; 121(9): 676–83

    PubMed  CAS  Google Scholar 

  130. O’Reilly RA. The binding of sodium warfarin to plasma albumin and its displacement by phenylbutazone. Ann N Y Acad Sci 1973; 226: 293–308

    PubMed  Article  Google Scholar 

  131. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45(6): 525–38

    PubMed  CAS  Article  Google Scholar 

  132. Thijssen HH, Baars LG, Janssen GM. Phenylbutazone-hydrox-ycoumarol interactions: effects on steady state disposition, hepatocellular distribution, and biliary excretion of (S)-ace-nocoumarol in rats. Drag Metab Dispos 1988; 16(5): 744–8

    CAS  Google Scholar 

  133. O’Reilly RA. Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon. Arch Intern Med 1982; 142(9): 1634–7

    PubMed  Article  Google Scholar 

  134. Schmidt W, Jahnchen E. Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats. J Pharmacokinet Biopharm 1979; 7(6): 643–63

    PubMed  CAS  Google Scholar 

  135. Serlin MJ, Challiner M, Park BK, et al. Cimetidine potentiates the anticoagulant effect of warfarin by inhibition of drag metabolism. Biochem Pharmacol 1980; 29(13): 1971–2

    PubMed  CAS  Article  Google Scholar 

  136. Serlin MJ, Sibeon RG, Mossman S, et al. Cimetidine: interaction with oral anticoagulants in man. Lancet 1979; II(8138): 317–9

    Article  Google Scholar 

  137. Gill TS, Hopkins KJ, Bottomley J, et al. Cimetidine-nicoumalone interaction in man: stereochemical considerations. Br J Clin Pharmacol 1989; 27(4): 469–74

    PubMed  CAS  Article  Google Scholar 

  138. Kroon de Boer A, Hoogkamer JF, et al. Detection of drug interactions with single dose acenocoumarol: new screening method?. Int J Clin Pharmacol Ther Toxicol 1990; 28(8): 355–60

    Google Scholar 

  139. Niopas I, Toon S, Aarons L, et al. The effect of Cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans. Eur J Clin Pharmacol 1999; 55(5): 399–404

    PubMed  CAS  Article  Google Scholar 

  140. Harenberg J, Staiger C, de Vries JX, et al. Cimetidine does not increase the anticoagulant effect of phenprocoumon. Br J Clin Pharmacol 1982; 14(2): 292–3

    PubMed  CAS  Article  Google Scholar 

  141. Harenberg J, Zimmermann R, Staiger C, et al. Lack of effect of Cimetidine on action of phenprocoumon. Eur J Clin Pharmacol 1982; 23(4): 365–7

    PubMed  CAS  Article  Google Scholar 

  142. He M, Kunze KL, Trager WF. Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites. Drug Metab Dispos 1995; 23(6): 659–63

    PubMed  CAS  Google Scholar 

  143. Eriksson UG, Mandema JW, Karlsson MO, et al. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis. Clin Pharmacokinet 2003; 42(7): 687–701

    PubMed  CAS  Article  Google Scholar 

  144. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003; 31(3): 294–305

    PubMed  CAS  Article  Google Scholar 

  145. Eriksson UG, Bredberg U, Gislen K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003; 59(1): 35–43

    PubMed  CAS  Google Scholar 

  146. Sarich Teng R, Peters GR, et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003; 42(5): 485–92

    Article  Google Scholar 

  147. Schutzer KM, Wall U, Lonnerstedt C, et al. Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crashed tablets or dissolved formulation. Curr Med Res Opin 2004; 20(3): 325–31

    PubMed  Article  CAS  Google Scholar 

  148. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 2003; 109(1): S9–15

    PubMed  CAS  Article  Google Scholar 

  149. Schutzer KM, Wall U, Lonnerstedt C, et al. Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crashed tablets or dissolved formulation. Curr Med Res Opin 2004; 20(3): 325–31

    PubMed  Article  CAS  Google Scholar 

  150. Bredberg E, Andersson Frison L, et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003; 42(8): 765–77

    PubMed  CAS  Article  Google Scholar 

  151. Johansson LC, Andersson M, Fager G, et al. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003; 42(5): 475–84

    PubMed  CAS  Article  Google Scholar 

  152. Wahlander Eriksson-Lepkowska M, Frison L, et al. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42(8): 755–64

    Article  Google Scholar 

  153. Sarich TC, Schutzer KM, Wollbratt M, et al. No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers. J Clin Pharmacol 2004; 44(8): 935–41

    PubMed  CAS  Article  Google Scholar 

  154. Fager G, Cullberg M, Eriksson-Lepkowska M, et al. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid. Eur J Clin Pharmacol 2003; 59(4): 283–9

    PubMed  CAS  Article  Google Scholar 

  155. Sarich TC, Schutzer KM, Dorani H, et al. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran. J Clin Pharmacol 2004; 44(8): 928–34

    PubMed  CAS  Article  Google Scholar 

  156. Sarich TC, Johansson S, Schutzer KM, et al. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol. J Clin Pharmacol 2004; 44(4): 388–93

    PubMed  CAS  Article  Google Scholar 

  157. Teng R, Sarich TC, Eriksson UG, et al. A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor. J Clin Pharmacol 2004; 44(9): 1063–71

    PubMed  CAS  Article  Google Scholar 

  158. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42(4): 381–92

    PubMed  CAS  Article  Google Scholar 

  159. Eriksson UG, Johansson S, Attman PO, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42(8): 743–53

    PubMed  CAS  Article  Google Scholar 

  160. 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 2002; 137(8): 648–55

    PubMed  CAS  Google Scholar 

  161. 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 2003; 349(18): 1703–12

    PubMed  CAS  Article  Google Scholar 

  162. Olsson SB, Executive Steering Committee on behalf of the SIIII. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362(9397): 1691–8

    PubMed  CAS  Article  Google Scholar 

  163. Petersen P, Grind M, Adler J, et al. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: SPORTIF II. A dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003; 41(9): 1445–51

    PubMed  CAS  Article  Google Scholar 

  164. MacAllister R, Hingorani AD, Casas JP. Ximelagatran or warfarin in atrial fibrillation?. Lancet 2004; 363(9410): 735–6

    PubMed  Article  Google Scholar 

  165. Stollberger C, Finsterer J. Ximelagatran or warfarin in atrial fibrillation?. Lancet 2004; 363(9410): 734–5

    PubMed  Article  Google Scholar 

  166. Eikelboom J, Hankey G. Ximelagatran or warfarin in atrial fibrillation [letter]?. Lancet 2004; 363(9410): 734

    PubMed  Article  Google Scholar 

  167. Eikelboom JW, Hankey GJ. The beginning of the end of warfarin?. Med J Aust 2004; 180(11): 549–51

    PubMed  Google Scholar 

  168. Cromheecke ME, Levi M, Colly LP, et al. Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison. Lancet 2000; 356(9224): 97–102

    PubMed  CAS  Article  Google Scholar 

  169. Bastholm Rahmner P, Andersen-Karlsson E, Arnhjort T, et al. Physicians’ perceptions of possibilities and obstacles prior to implementing a computerised drug prescribing support system. Int J Health Care Qual Assur Inc Leadersh Health Serv 2004; 17(4-5): 173–9

    PubMed  CAS  Google Scholar 

  170. Ito RK, Demers LM. Pharmacogenomics and pharmacogenetics: future role of molecular diagnostics in the clinical diagnostic laboratory. Clin Chem 2004; 50(9): 1526–7

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

The author received a research scholarship provided by the German Research Council, Bonn, Germany (Uf 6/1-2) and has no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mike Ufer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ufer, M. Comparative Pharmacokinetics of Vitamin K Antagonists. Clin Pharmacokinet 44, 1227–1246 (2005). https://doi.org/10.2165/00003088-200544120-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200544120-00003

Keywords

  • Warfarin
  • Human Liver Microsome
  • Intrinsic Clearance
  • Phenprocoumon
  • Acenocoumarol