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Chemical Compound Review

S-WARFARIN     2-hydroxy-3-[(1S)-3-oxo-1- phenyl...

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Disease relevance of S-WARFARIN


High impact information on S-WARFARIN

  • BACKGROUND: The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin [4].
  • The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems [4].
  • 0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined [5].
  • 5'-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients [6].
  • RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%) [7].

Chemical compound and disease context of S-WARFARIN


Biological context of S-WARFARIN

  • In addition, Japanese patients heterozygous for the CYP2C9*3 genotype (n = 4) showed a significantly (P <.05) reduced unbound oral clearance for S-warfarin, by 63%, as compared with Japanese patients possessing the homozygous CYP2C9*1 genotype [9].
  • BACKGROUND: Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme (CYP2C9) (allelic variants 2C9*2 and 2C9*3 ) linked with impaired metabolism of the potent enantiomere S-warfarin [10].
  • Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations [11].
  • In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant [12].
  • CYP2C9 catalyses the biotransformation of the oral anticoagulants S-warfarin and R- and S-acenocoumarol [13].

Anatomical context of S-WARFARIN


Associations of S-WARFARIN with other chemical compounds


Gene context of S-WARFARIN

  • 2. Troglitazone (5 microM) significantly inhibited CYP2C8-dependent paclitaxel 6alpha-hydroxylation and CYP2C9-dependent S-warfarin 7-hydroxylation [23].
  • OBJECTIVE: Our objective was to investigate population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically matched Caucasian and Japanese patients by using the unbound oral clearance of S-warfarin as an in vivo phenotypic trait measure [9].
  • These reactions were catalyzed by CYP3A4, based on data derived from immunoinhibitory studies, with 4'-hydroxylation being preferentially associated with S-warfarin and 10-hydroxylation with R-warfarin [24].
  • Although P450 2C9 substrate S-warfarin partially protected against inactivation, reactive oxygen scavengers such as superoxide dismutase and catalase did not prevent inactivation [25].
  • The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h [26].

Analytical, diagnostic and therapeutic context of S-WARFARIN


  1. The stereoselective interaction of warfarin and metronidazole in man. O'Reilly, R.A. N. Engl. J. Med. (1976) [Pubmed]
  2. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Loebstein, R., Vecsler, M., Kurnik, D., Austerweil, N., Gak, E., Halkin, H., Almog, S. Clin. Pharmacol. Ther. (2005) [Pubmed]
  3. Microbial transformations of warfarin: stereoselective reduction by Nocardia corallina and Arthrobacter species. Davis, P.J., Rizzo, J.D. Appl. Environ. Microbiol. (1982) [Pubmed]
  4. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Aithal, G.P., Day, C.P., Kesteven, P.J., Daly, A.K. Lancet (1999) [Pubmed]
  5. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Sconce, E.A., Khan, T.I., Wynne, H.A., Avery, P., Monkhouse, L., King, B.P., Wood, P., Kesteven, P., Daly, A.K., Kamali, F. Blood (2005) [Pubmed]
  6. 5'-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients. Takahashi, H., Ieiri, I., Wilkinson, G.R., Mayo, G., Kashima, T., Kimura, S., Otsubo, K., Echizen, H. Blood (2004) [Pubmed]
  7. Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer. Camidge, R., Reigner, B., Cassidy, J., Grange, S., Abt, M., Weidekamm, E., Jodrell, D. J. Clin. Oncol. (2005) [Pubmed]
  8. Ticrynafen-racemic warfarin interaction: hepatotoxic or stereoselective? O'Reilly, R.A. Clin. Pharmacol. Ther. (1982) [Pubmed]
  9. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Takahashi, H., Wilkinson, G.R., Caraco, Y., Muszkat, M., Kim, R.B., Kashima, T., Kimura, S., Echizen, H. Clin. Pharmacol. Ther. (2003) [Pubmed]
  10. Interindividual variability in sensitivity to warfarin--Nature or nurture? Loebstein, R., Yonath, H., Peleg, D., Almog, S., Rotenberg, M., Lubetsky, A., Roitelman, J., Harats, D., Halkin, H., Ezra, D. Clin. Pharmacol. Ther. (2001) [Pubmed]
  11. Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans. Awni, W.M., Hussein, Z., Granneman, G.R., Patterson, K.J., Dubé, L.M., Cavanaugh, J.H. Clinical pharmacokinetics. (1995) [Pubmed]
  12. Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. King, B.P., Khan, T.I., Aithal, G.P., Kamali, F., Daly, A.K. Pharmacogenetics (2004) [Pubmed]
  13. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Kirchheiner, J., Ufer, M., Walter, E.C., Kammerer, B., Kahlich, R., Meisel, C., Schwab, M., Gleiter, C.H., Rane, A., Roots, I., Brockmöller, J. Pharmacogenetics (2004) [Pubmed]
  14. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Yamazaki, H., Shimada, T. Biochem. Pharmacol. (1997) [Pubmed]
  15. Vitamin K 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydroxycoumarin anticoagulant activity. Thijssen, H.H., Baars, L.G., Vervoort-Peters, H.T. Br. J. Pharmacol. (1988) [Pubmed]
  16. The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat. Thijssen, H.H., Janssen, C.A., Drittij-Reijnders, M.J. Biochem. Pharmacol. (1986) [Pubmed]
  17. Characterization of the T-cell response in a patient with phenindione hypersensitivity. Naisbitt, D.J., Farrell, J., Chamberlain, P.J., Hopkins, J.E., Berry, N.G., Pirmohamed, M., Park, B.K. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  18. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Scordo, M.G., Pengo, V., Spina, E., Dahl, M.L., Gusella, M., Padrini, R. Clin. Pharmacol. Ther. (2002) [Pubmed]
  19. Target-based warfarin pharmacokinetics in the rat: the link with the anticoagulant effect. Thijssen, H.H., Janssen, Y.P. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  20. Exocyclic-keto reductase activities for progesterone and S-warfarin in hepatic microsomes from adult male rats. Apanovitch, D., Kitareewan, S., Walz, F.G. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  21. Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R ratios, accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers. Ma, J.D., Nafziger, A.N., Kashuba, A.D., Kim, M.J., Gaedigk, A., Rowland, E., Kim, J.S., Bertino, J.S. Journal of clinical pharmacology. (2004) [Pubmed]
  22. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Yasar, U., Eliasson, E., Dahl, M.L., Johansson, I., Ingelman-Sundberg, M., Sjöqvist, F. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  23. In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone. Yamazaki, H., Suzuki, M., Tane, K., Shimada, N., Nakajima, M., Yokoi, T. Xenobiotica (2000) [Pubmed]
  24. In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4'- and 10-hydroxywarfarin. Ngui, J.S., Chen, Q., Shou, M., Wang, R.W., Stearns, R.A., Baillie, T.A., Tang, W. Drug Metab. Dispos. (2001) [Pubmed]
  25. Mechanism-based inactivation of human recombinant P450 2C9 by the nonsteroidal anti-inflammatory drug suprofen. O'Donnell, J.P., Dalvie, D.K., Kalgutkar, A.S., Obach, R.S. Drug Metab. Dispos. (2003) [Pubmed]
  26. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Lilja, J.J., Backman, J.T., Neuvonen, P.J. British journal of clinical pharmacology. (2005) [Pubmed]
  27. Warfarin enantiomer disposition: determination by stereoselective radioimmunoassay. Cook, C.E., Ballentine, N.H., Seltzman, T.B., Tallent, C.R. J. Pharmacol. Exp. Ther. (1979) [Pubmed]
  28. Comparative pharmacokinetics of coumarin anticoagulants. XLIX: Nonlinear tissue distribution of S-warfarin in rats. Cheung, W.K., Levy, G. Journal of pharmaceutical sciences. (1989) [Pubmed]
  29. Supercritical fluid chromatography-tandem mass spectrometry for fast bioanalysis of R/S-warfarin in human plasma. Coe, R.A., Rathe, J.O., Lee, J.W. Journal of pharmaceutical and biomedical analysis. (2006) [Pubmed]
  30. The effects of 17 beta-oestradiol or testosterone on the response to S-warfarin in castrated male rats. Winn, M.J., Park, B.K. J. Pharm. Pharmacol. (1987) [Pubmed]
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