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.
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References
Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19(1): 97–107
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
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
Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005 Jan 15; 105(2): 453–63
Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation 2004; 110 (9 Suppl. 1): 119–26
Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119(90010): 108–121S
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
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
Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73(1): 67–74
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
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
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
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
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
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
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
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
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
Thijssen HH, Ritzen Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther 2003; 74_(1): 61–8
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
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
Meinertz T, Kasper W, Kahl C, et al. Anticoagulant activity of the enantiomers of acenocoumarol. Br J Clin Pharmacol 1978; 5(2): 187–8
Jahnchen E, Meinertz T, Gilfrich HJ, et al. The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther 1976; 20(3): 342–9
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Heimark LD, Trager WF. A stable isotope assay for phenprocoumon and its metabolites. Biomed Mass Spectrom 1985; 12(2): 67–71
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
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
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
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
Haustein KO, Huiler G. Pharmacokinetics of phenprocoumon. Int J Clin Pharmacol Ther 1994; 32(4): 192–7
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
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
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
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
Haustein KO. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon. Semin Thromb Hemost 1999; 25(1): 5–11
Thijssen HH, Hamulyak K, Willigers H. 4-Hydroxycoumarin oral anticoagulants: pharmacokinetics-response relationship. Thromb Haemost 1988; 60(1): 35–8
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
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
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
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
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
Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 1979; 4(1): 1–15
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
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
Lewis RJ, Trager WF. Warfarin metabolism in man: identification of metabolites in urine. J Clin Invest 1970; 49(5): 907–13
Lewis RJ, Trager WF. The metabolic fate of warfarin: studies on the metabolites in plasma. Ann N Y Acad Sci 1971; 179: 205–12
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
Fasco MJ, Dymerski PP, Wos JD, et al. A new warfarin metabolite: structure and function. J Med Chem 1978; 21(10): 1054–9
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
Kaminsky LS. Warfarin as a probe of cytochromes P-450 function. Drug Metab Rev 1989; 20(2-4): 479–87
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
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
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
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
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
Toon S, Low LK, Gibaldi M, et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986; 39(1): 15–24
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
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
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
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
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
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
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
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
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
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
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
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
Toon S, Heimark LD, Trager WF, et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985; 74(10): 1037–40
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
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
de Vries JX, Raedsch R, Volker U, et al. Biliary excretion of phenprocoumon and metabolites. Eur J Clin Pharmacol 1988; 35(4): 433–6
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
Pohl LR, Haddock RE, Trager WF. Biotransformation of phenprocoumon in the rat. J Med Chem 1975; 18(5): 519–23
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
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
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
Thijssen HH, Baars LG. The biliary excretion of acenocoumarol in the rat: stereochemical aspects. J Pharm Pharmacol 1987; 39(8): 655–7
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
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
Thijssen HH, Baars LG. Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?. Br J Clin Pharmacol 1983; 16(5): 491–6
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
Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics 2003; 13(5): 247–52
Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40(8): 587–603
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
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
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
Stubbins MJ, Harries LW, Smith G, et al. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6(5): 429–39
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
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
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
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
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
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
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
Morin S, Bodin L, Loriot MA, et al. Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther 2004; 75(5): 403–14
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
Verstuyft C, Morin S, Robert A, et al. Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers. Pharmacogenetics 2001; 11(8): 735–7
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
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
Mannucci PM. Genetic control of anticoagulation. Lancet 1999; 353(9154): 688–9
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
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
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
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
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
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
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
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
Harder S, Thurmann P. Clinically important drug interactions with anticoagulants: an update. Clin Pharmacokinet 1996; 30(6): 416–44
Freedman MD, Olatidoye AG. Clinically significant drag interactions with the oral anticoagulants. Drag Saf 1994; 10(5): 381–94
Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drags and food. Ann Intern Med 1994; 121(9): 676–83
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
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45(6): 525–38
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
O’Reilly RA. Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon. Arch Intern Med 1982; 142(9): 1634–7
Schmidt W, Jahnchen E. Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats. J Pharmacokinet Biopharm 1979; 7(6): 643–63
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
Serlin MJ, Sibeon RG, Mossman S, et al. Cimetidine: interaction with oral anticoagulants in man. Lancet 1979; II(8138): 317–9
Gill TS, Hopkins KJ, Bottomley J, et al. Cimetidine-nicoumalone interaction in man: stereochemical considerations. Br J Clin Pharmacol 1989; 27(4): 469–74
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
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
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
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
He M, Kunze KL, Trager WF. Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites. Drug Metab Dispos 1995; 23(6): 659–63
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
MacAllister R, Hingorani AD, Casas JP. Ximelagatran or warfarin in atrial fibrillation?. Lancet 2004; 363(9410): 735–6
Stollberger C, Finsterer J. Ximelagatran or warfarin in atrial fibrillation?. Lancet 2004; 363(9410): 734–5
Eikelboom J, Hankey G. Ximelagatran or warfarin in atrial fibrillation [letter]?. Lancet 2004; 363(9410): 734
Eikelboom JW, Hankey GJ. The beginning of the end of warfarin?. Med J Aust 2004; 180(11): 549–51
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
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
Ito RK, Demers LM. Pharmacogenomics and pharmacogenetics: future role of molecular diagnostics in the clinical diagnostic laboratory. Clin Chem 2004; 50(9): 1526–7
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.
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Ufer, M. Comparative Pharmacokinetics of Vitamin K Antagonists. Clin Pharmacokinet 44, 1227–1246 (2005). https://doi.org/10.2165/00003088-200544120-00003
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DOI: https://doi.org/10.2165/00003088-200544120-00003