Assays and applications in warfarin metabolism: What we know, how we know it and what we need to know

Expert Opinion on Drug Metabolism and Toxicology

Volumn 7, Issue 7, 2011, Pages 857-874

  Jones, Drew R ^a   Miller, Grover P ^a  

^a UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

Author keywords

applications; metabolism; methods; warfarin

Indexed keywords

BIOLOGICAL MARKER; CYTOCHROME P450; DRUG METABOLIZING ENZYME; GLUCURONOSYLTRANSFERASE; WARFARIN;

AEROBIC METABOLISM; ANALYTIC METHOD; CONJUGATION; DRUG ABSORPTION; DRUG METABOLISM; DRUG RESPONSE; DRUG STRUCTURE; ENANTIOMER; ENZYME THERAPY; FLUORESCENCE; GAS CHROMATOGRAPHY; HUMAN; HYDROLYSIS; ISOMER; LIQUID; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; METABOLITE; NONHUMAN; PHENOTYPE; PRECIPITATION; REVIEW; THIN LAYER CHROMATOGRAPHY; THROMBOEMBOLISM; UNSPECIFIED SIDE EFFECT;

ANTICOAGULANTS; BIOLOGICAL MARKERS; CHROMATOGRAPHY, GAS; CHROMATOGRAPHY, THIN LAYER; CYTOCHROME P-450 ENZYME SYSTEM; GLUCURONOSYLTRANSFERASE; HUMANS; MASS SPECTROMETRY; METABOLIC NETWORKS AND PATHWAYS; PHENOTYPE; WARFARIN;

EID: 79959201864     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2011.576247     Document Type: Review

References (93)

1. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin k antagonists. Chest 2008;7(Suppl 6):160S-98S
2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007;167(13):1414-19 (Pubitemid 47052441)
3. Kresge N, Simoni RD, Hill RL. Hemorrhagic sweet clover disease, dicumarol, and warfarin: the work of Karl Paul link. J Biol Chem 2005;280(8):e5
4. Overman R, Stahmann, MA, et al. Studies on the hemorrhagic sweet clover disease: XIII. Anticoagulant activity and structure in the 4-hydroxycoumarin group. J Biol Chem 1944;153:5-24
5. Gebauer M. Synthesis and structure-activity relationships of novel warfarin derivatives. Bioorg Med Chem 2007;15(6):2414-20 (Pubitemid 46240909)
6. Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther 1974;15(4):424-30
7. O'Reilly RA. Vitamin K and the oral anticoagulant drugs. Annu Rev Med 1976;27(1):245-61
8. Breckenridge A. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol 1978;15(1):19-26 (Pubitemid 8262977)
9. O'Reilly R. Warfarin metabolism and drug-drug interactions. In: Wessler S, Becker CG, Nemerson Y, editors, The new dimensions of warfarin prophylaxis: advances in experimental medicine and biology. NY, Plenum, New York; 1986. p. 205-12
10. Toon S, Low LK, Gibaldi M, et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986;39(1):15-24 (Pubitemid 16166960)
11. Lewis R, Trager WF. Warfarin metabolism in man: identification of metabolites in urine. J Clin Invest 1970;49(5):907-13
12. Lewis R, Trager WF, Robinson AJ, Chan KK. Warfarin metabolites: the anticoagulant activity and pharmacology of warfarin alcohols. J Lab Clin Med 1973;81(6):925-31
13. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67-74 (Pubitemid 26425815)
14. Rettie A, 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
15. Miners J, Birkett, DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998;45:525-38 (Pubitemid 28270907)
16. 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;8:365-73 (Pubitemid 28475300)
17. Brian WR, Sari M-A, Iwasaki M, et al. Catalytic activities of human liver cytochrome P-450 IIIA4 expressed in Saccharomyces cerevisiae. Biochemistry 1990;29:11280-92
18. Ngui JS, Chen Q, Shou M, et al. In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4′- and 10-Hydroxywarfarin. Drug Metab Dispos 2001;29(6):877-86
19. Jones DR, Kim SY, Boysen G, et al. Contribution of Three CYP3A Isoforms to Metabolism of R- and S-Warfarin. Drug Metab Lett 2010;4(4):213-9
20. Kaminsky L, de Morais S, Faletto M, et al. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 1993;43(2):234-9 (Pubitemid 23055067)
21. 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
22. Locatelli I, Kmetec V, Mrhar A, et al. Determination of warfarin enantiomers and hydroxylated metabolites in human blood plasma by liquid chromatography with achiral and chiral separation. J Chromatogr B 2005;818(2):191-8 (Pubitemid 40331823)
23. Miller GP, Jones DR, Sullivan SZ, et al. Assessing cytochrome P450 and UDP-glucuronosyltransferase contributions to warfarin metabolism in humans. Chem Res Toxicol 2009;22(7):1239-45
24. Zhang Z, Fasco MJ, Huang Z, et al. Human cytochromes P450 1A1 and 1A2: R-warfarin as a probe. Drug Metab Dispos 1995;23:1339-45 (Pubitemid 26007840)
25. 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;24:610-14 (Pubitemid 26146703)
26. Jones D, Boysen G, Miller GP. Novel dual-phase ultra performance liquid chromatography - tandem mass spectrometry assay for profiling enantiomeric hydroxywarfarins and warfarin in human plasma. J Chromatogr B. Doi: 10.1016/j.jchromb.2011.03.022. Available from: http://www.sciencedirect.com/ science?-ob=ArticleURL&-udi=B6X0P-52F6PGV-1&-user=1496715&- coverDate=03%2F21% 2F2011&-alid=1708405284&-rdoc=1&-fmt=high&- orig=search&-origin=search&-zone=rslt-list-item &-cdi=7220&- sort=r&-st=13&-docanchor=&view=c&-ct=14&-acct= C000053083&-version=1 &-urlVersion=0&-userid=1496715&md5= 42753481053417e38566f5d5696c225e&searchtype=a
27. Miller G. Warfarin therapy: how the less interesting half just got interesting. J Thromb Haemost 2010;8(12):2705-7
28. Lee S, Hwang HJ, Kim JM, et al. CYP2C19 polymorphism in Korean patients on warfarin therapy. Arch Pharm Res 2007;30(3):344-9
29. Obayashi K, Nakamura K, Kawana J, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006;80(2):169-78 (Pubitemid 44160690)
30. Jorgensen AL, Al-Zubiedi S, Zhang JE, et al. Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics 2009;19(10):800-12
31. Ritter JK. Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact 2000;129(1-2):171-93 (Pubitemid 32061059)
32. Jansing R, Chao E, Kaminsky L. Phase II metabolism of warfarin in primary culture of adult rat hepatocytes. Mol Pharmacol 1992;41(1):209-15
33. Zielinska A, Lichti CF, Bratton S, et al. Glucuronidation of monohydroxylated warfarin metabolites by human liver microsomes and human recombinant UDP-glucuronosyltransferases. J Pharmacol Exp Ther 2008;324(1):139-48 (Pubitemid 350294175)
34. Miller GP, Lichti CF, Zielinska AK, et al. Identification of hydroxywarfarin binding site in human UDP glucuronosyltransferase 1A10: phenylalanine90 is crucial for the glucuronidation of 6- and 7-Hydroxywarfarin but Not 8-Hydroxywarfarin 10.1124/dmd.108.022863. Drug Metab Dispos 2008;36(11):2211-18
35. Vesell E, Shively CA. Liquid chromatographic assay of warfarin: similarity of warfarin half-lives in human subjects. Science 1974;184(135):466-8
36. Kaiser D, Martin RS. GLC determination of warfarin in human plasma. J Pharm Sci 1974;63(10):1579-81
37. Midha K, McGilveray IJ, Cooper JK. GLC determination of plasma levels of warfarin. J Pharm Sci 1974;63(11):1725-9
38. Bjornsson T, Blaschke TF, Meffin PJ. High-pressure liquid chromatographic analysis of drugs in biological fluids I. Warfarin. J Pharm Sci 1977;66(1):142-4 (Pubitemid 8022215)
39. Banfield C, Rowland M. Stereospecific high-performance liquid chromatographic analysis of warfarin in plasma. J Pharm Sci 1983;72(8):921-4 (Pubitemid 13040649)
40. Banfield C, Rowland M. Stereospecific fluorescence high-performance liquid chromatographic analysis of warfarin and its metabolites in plasma and urine. J Pharm Sci 1984;73:1392-6 (Pubitemid 14021890)
41. 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 (Pubitemid 24197150)
42. Duffield A, Duffield PH, Birkett DJ, et al. Plasma quantitation of warfarin and warfarin alcohol by gas chromatography chemical ionization mass spectrometry in patients on warfarin maintenance therapy. Biomed Mass Spectrom 1979;6(5):208-11 (Pubitemid 9198011)
43. Duffield P, Duffield AM, Kennedy M, et al. Warfarin and warfarin-alcohol levels in anticoagulated patients. Aust NZ J Med 1979;9(5):534-7 (Pubitemid 10207846)
44. Bush E, Low LK, Trager WF. A sensitive and specific stable isotope assay for warfarin and its metabolites. Biomed Mass Spectrom 1983;10(7):395-8
45. 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 on-line circular dichroism detection. J Chromatogr B Biomed Sci Appl 1997;701(1):71-80 (Pubitemid 27473961)
46. 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;253:7813-20
47. Fasco M, Cashin MJ, Kaminsky LS. A novel method for the quantitation of warfarin and its metabolites in plasma. J Liq Chromatogr 1979;2(4):565-75 (Pubitemid 9162891)
48. Ufer M, Kammerer B, Kirchheiner J, et al. Determination of phenprocoumon, warfarin and their monohydroxylated metabolites in human plasma and urine by liquid chromatography-mass spectrometry after solid-phase extraction. J Chromatogr B 2004;809(2):217-26 (Pubitemid 39094697)
49. Spink DC, Aldous KM, Kaminsky LS. Analysis of oxidative warfarin metabolites by thermospray high-performance liquid chromatography/mass spectrometry. Anal Biochem 1989;177:307-13 (Pubitemid 19088264)
50. Henne K, Gaedigk A, Gupta G, et al. Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype. J Chromatogr B Biomed Sci Appl 1998;710:143-8 (Pubitemid 28318147)
51. Zuo Z, Wo SK, Lo CMY, et al. Simultaneous measurement of S-warfarin, R-warfarin, S-7-hydroxywarfarin and R-7-hydroxywarfarin in human plasma by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2010;52(2):305-10
52. Miura M, Okuyama S, Kato S, et al. Simultaneous determination of warfarin and 7-hydroxywarfarin enantiomers by high-performance liquid chromatography with ultraviolet detection. Ther Drug Monit 2011;33(1):108-14
53. Lang D, Bocker R. Highly sensitive and specific high-performance liquid chromatographic analysis of 7-hydroxywarfarin, a marker for human cytochrome P-4502C9 activity. J Chromatogr 1995;672:305-9
54. Chu Y-Q, Wainer IW. The measurement of warfarin enantiomers in serum using coupled achiral/chiral, high-performance liquid chromatography (HPLC). Pharm Res 1988;5(10):680-3 (Pubitemid 18263619)
55. Barker W, Hermodson M, Link K. The metabolism of 4-C14-warfarin sodium by rat. J Pharmacol Exp Ther 1970;171(2):307-13
56. Lewis R, Ilnicki LP, Carlstrom M. The assay of warfarin in plasma or stool. Biochem Med 1970;4(5):376-82
57. Lewis R, 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
58. Zhang Z-Y, King BM, Wong YN. Quantitative liquid chromatography/mass spectrometry/mass spectrometry warfarin assay for in vitro cytochrome P450 studies. Anal Biochem 2001;298(1):40-9 (Pubitemid 33030119)
59. Turpault S, Brian W, Van Horn R, et al. Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 2009;68(6):928-35
60. Kwon MJ, Kim HJ, Kim JW, et al. Determination of plasma warfarin concentrations in Korean patients and its potential for clinical application. Korean J Lab Med 2009;29(6):515-23
61. Kulkarni UP, Swar BD, Karnad DR, et al. A pilot study of the association of pharmacokinetic and pharmacodynamic parameters of warfarin with the dose in patients on long-term anticoagulation. Br J Clin Pharmacol 2008;65(5):787-90 (Pubitemid 351535093)
62. 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 (Pubitemid 8022068)
63. de Vries J, Kymber KA. Thermospray and particle beam liquid chromatographic-mass spectrometric analysis of coumarin anticoagulants. J Chromatogr 1991;562:31-8
64. Hermodson M. Biochemical studies on warfarin. University of Wisconsin, Madison, WI; 1968
65. Howald W, Bush ED, Trager WF, et al. A stable isotope assay for pseudoracemic warfarin from human plasma samples. Biomed Mass Spectrom 1980;7(1):35-40 (Pubitemid 10121809)
66. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet(TM) systematic review and meta-analysis. Genet Med 2005;7(2):97-104 (Pubitemid 40261834)
67. Steward DJ, Haining RL, Henne KR, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997;7:361-7 (Pubitemid 27427545)
68. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 2003;3(4):202-14 (Pubitemid 37167925)
69. Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007;121(1):23-34 (Pubitemid 46421137)
70. Lenzini P, Wadelius M, Kimmel S, et al. Integration of Genetic, Clinical, and INR Data to Refine Warfarin Dosing. Clin Pharmacol Ther 2010;87(5):572-8
71. Jones D, Kim SY, Guderyon M, et al. Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-Warfarin. Chem Res Toxicol 2010;23(5):939-45
72. Rulcova A, Prokopova I, Krausova L, et al. Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes. J Thromb Haemost 2010;8(12):2708-17
73. Miller G. Warfarin therapy: how the less interesting half just got interesting. J Thromb Haemost 2010;8(12):2705-7
74. Leeder J, Gaedigk A, Gupta G, et al. Determinants of Warfarin S:R Ratio in Orthopedic Surgery (OS) Patients. Clin Pharmacol Ther 1999;65:194
75. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004;32(11):1201-8 (Pubitemid 39410902)
76. Frye RF. Probing the World of Cytochrome P450 Enzymes. Mol Interv 2004;4(3):157-62 (Pubitemid 38960844)
77. Kaminsky LS. Warfarin as a probe of cytochromes P-450 function. Drug Metab Rev 1989;20:479-87 (Pubitemid 19277712)
78. Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens, and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270:414-23 (Pubitemid 24229655)
79. Kim J, Nafziger AN, Gaedigk A, et al. Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe. J Clin Pharmacol 2001;41(7):715-22 (Pubitemid 32612434)
80. Chainuvati S, Nafziger AN, Leeder JS, et al. Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase- 2, and xanthine oxidase activities with the [ldquo]Cooperstown 5+1 cocktail[rdquo] [ast]. Clin Pharmacol Ther 2003;74(5):437-47 (Pubitemid 37357722)
81. Shelepova T, Nafziger AN, Victory J, et al. Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated cooperstown 5+1 Cocktail. J Clin Pharmacol 2005;45(12):1413-21 (Pubitemid 41642445)
82. O'Sullivan TA, Wang JP, Unadkat JD, et al. Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced. Clin Pharmacol Ther 1993;54:323-8
83. Wang J, Unadkat JD, McNamara S, et al. Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis. Clin Pharmacol Ther 1994;55(5):528-34
84. Jones D, Moran JH, Miller GP. Warfarin and UDPglucuronosyltransferases: writing a new chapter of metabolism. Drug Metab Rev 2010;42(1):53-9
85. Harper T, Brassil P. Reaction phenotyping: current industry efforts to identify enzymes responsible for metabolizing drug candidates. AAPS J 2008;10(1):200-7
86. Lappin G, Kuhnz W, Jochemsen R, et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs[ast]. Clin Pharmacol Ther 2006;80(3):203-15 (Pubitemid 44313903)
87. de Vries J, Volker U. Separation of the enantiomers of phenprocoumon and warfarin by high-performance liquid chromatography using a chiral stationary phase. Determination of the enantiomeric ratio of phenprocoumon in human plasma and urine. J Chromatogr 1989;493(1):149-56 (Pubitemid 19216030)
88. Moser AC, Kingsbury C, Hage DS. Stability of warfarin solutions for drug-protein binding measurements: spectroscopic and chromatographic studies. J Pharm Biomed Anal 2006;41(4):1101-9 (Pubitemid 43775892)
89. 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;63:519-28 (Pubitemid 28277273)
90. Guo Y, Weller P, Farrell E, et al. In silico pharmacogenetics of warfarin metabolism. Nat Biotech 2006;24(5):531-6
91. Edelbroek P, van Kempen GM, Hessing TJ, de Wolff FA. 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 (Pubitemid 20276122)
92. Turpault S, Brian W, Van Horn R, et al. Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 2009;68(6):928-35
93. Malakova J, Pavek P, Svecova L, et al. New high-performance liquid chromatography method for the determination of (R)-warfarin and (S)-warfarin using chiral separation on a glycopeptide-based stationary phase. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(27):3226-30