Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Lewis, Richard J.; Trager, William; Chan, Kenneth K.; Breckenridge, AM; Orme, M.; Roland, Malcolm; Schary, William

doi:10.1172/jci107711

Cited by 274 publications

(83 citation statements)

References 28 publications

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“…The enantiomers of warfarin follow different metabolic routes in man (Lewis et al, 1974;Toon et al, 1987). The S-enantiomer is mainly hydroxylated to form 7-hydroxywarfarin (Figure 1), whereas R-warfarin is mainly reduced to its RS alcohol and hydroxylated at the 6-position.…”

Section: Introductionmentioning

confidence: 99%

“…Various P450 isozymes, displaying different regio-and stereoselectivities, have been shown to be involved in the metabolism of warfarin (Guengerich et al, 1982;Rettie et al, 1992). The variety of warfarin metabolizing P450 isozymes offers an explanation for the stereoselective (pharmacokinetic) drug-interactions with R-warfarin (Choonara et al, 1986;Toon et al, 1987;Sutfin et al, 1989;), S-warfarin (Lewis et al, 1974;O'Reilly, 1980), as well as non-stereoselective interactions (O'Reilly et al, 1987) that have been observed. The human cytochrome P450 2C9 has been shown to be a S-warfarin 7-(and to a lesser extent 6-) hydroxylase, and is claimed to be responsible for the bulk of S-warfarin clearance in vivo (Rettie et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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1 To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2 The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6-and 7-position (accounting for 63 to 99% of the metabolic clearances).3 Due to the lower Km values of R-and S-acenocoumarol and higher Vma. values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4 The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol.5 Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P <0.025), the 6-and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6 Sulphaphenazole competitively inhibits the 7-and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R-and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 JAM).7 Omeprazole partly (40-80%) inhibits the 6-and 7-hydroxylation of R-warfarin (Ki = 99 and 117 pM) and of R-(Ki = 219 and 7.2 jAM) and S-acenocoumarol (Ki = 6.1 and 7.7 JiM) but not S-warfarin in a competitive manner. 8 Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine. 9 The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7-and 6-hydroxylase).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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“…Several authors have shown that the enantiomers of warfarin and phenprocoumon differ in their pharmacokinetic characteristics and metabolic fate, as well as in their anticoagulant activity in man (O'Reilly, 1971;Hewick & McEwen, 1973;Lewis et al, 1973;Breckenridge et al, 1974;O'Reilly, 1974;Levy, O'Reilly & Wingard, 1974;Lewis et al, 1974;Sellers & Koch-Weser, 1975;Hewick & Shepherd, 1976;Jahnchen et al, 1976;Kelly & O'Malley, 1979). The S(-) enantiomers of these two drugs are twice to five times as potent as the R(+) enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the enantiomers of acenocoumarol in man.

Godbillon¹,

Richard²,

Gérardin³

et al. 1981

Brit J Clinical Pharma

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1 The pharmacokinetics of R(+)-, S(-)-and R,S(+)-acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(-). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(-) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half-life of S(-) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume ofdistribution Vdss of S(-) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(-) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.

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“…It was demonstrated that the drug inhibits the metabolism of S-warfarin (more potent enantiomer) while increasing the rate of elimination of R-warfarin. The net effect was an increased anticoagulant response to a single dose of racemic warfarin, but no apparent change in the racemic warfarin half-life 155 . The restricted use of phenylbutazone greatly reduces the chance of this potentially fatal interaction being observed.…”

Section: Drugs Causing Inhibition Of Metabolismmentioning

confidence: 96%

Interactions of Warfarin

Rehulková¹

2001

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropriate examples. The interactions with drugs, medicinal herbs and foods are summarised. 28Cholestyramine binds vitamin K in the gut, thus preventing its absorption 18 . It also decreases the absorption and may interrupt the enterohepatic recirculation of warfarin, resulting in a reduced anticoagulant effect 19,20 .Colestipol does not affect the absorption of warfarin. When colestipol is administered with warfarin, no depressant effects on blood levels are seen 21 . Drugs affecting receptor sensitivityEstrogens increase the synthesis of various clotting factors and may thus reduce the effect of anticoagulants 22, 23 . Oral contraceptives increase clotting factor concentrations and inhibit warfarin metabolism. The net effect depends on balance between these factors. Oral contraceptives are generally contraindicated in most patients taking warfarin since they are trombogenic 1, 24 .Steroids with anabolic or androgenic properties, such as oxymetholone 25, 26, 27 , stanozolol 28, 29 and danazol 30, 31, 32 , may potentiate the action of warfarin allegedly by reducing clotting factor synthesis. The 17-alpha-alkylated steroids appear to be more likely to induce this reaction than the non-substituted steroids 25, 26, 27, 33 . However, there has been a report of topically applied testosterone, which does not have 17-alpha-alkyl substituent, enhancing warfarin 34 .Diuretics may antagonise the action of warfarin by two pharmacodynamic mechanisms 18 : (a) patients in cardiac failure have impaired clotting factor synthesis due to hepatic congestion -correction of this state leads to increased clotting factor synthesis; (b) diuretics also reduce the plasma volume producing an increased concentration of clotting factors which may alter the anticoagulant effect of warfarin 35 . Chlorthalidone 36 and spironolactone 35 have both been associated with a reduction of warfarin activity probably as a consequence of diuresis concentrating the circulating clotting factors. Bumetanide, furosemide and thiazides appear to have no effect on warfarin 23 .Certain cephalosporines, such as cefotetan, cefamandole, cefoperazone, or moxalactam may cause marked hypoprothrombinemia and/or prolonged bleeding time at concurrent use with warfarin 38, 39, 40, 41 . The main mechanism of interaction consists in decreasing synthesis of vitamin K-dependent clotting factors.Clofibrate may potentiate warfarin action, probably by altering receptor sensitivity 23, 37 . Although clofibrate displaces warfarin from albumin binding sites this does not appear to be a principal mechanism of the interaction 42 .Drugs altering thyroid function may affect anticoagulant control, since rates of synthesis and degradation of clotting factors are dependent on thyroid function 7 . Thyroid compounds do enhance the activity of oral anticoagulants by increased metabolism of clotting factors 12 . Dextrothyroxine increases the anticoagulant effect of warfarin ...

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Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Cited by 274 publications

References 28 publications

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Pharmacokinetics of the enantiomers of acenocoumarol in man.

Interactions of Warfarin

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