Binding of Nonsteroidal Anti-Inflammatory Agents and Their Effect on Binding of Racemic Warfarin and Its Enantiomers to Human Serum Albumin

Diana, Frank J.; Veronich, Karen; Kapoor, A.

doi:10.1002/jps.2600780304

Cited by 62 publications

(41 citation statements)

References 30 publications

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“…The finding that the enantiomers bind in essentially the same way to HSA is consistent with the observation that they have similar binding affinities for the protein. At 25°C, close to the temperature of our diffraction data collection, the R-(ϩ) and S-(Ϫ) enantiomers have dissociation constants of 3.8 and 2.9 M, respectively (21), although the difference is slightly more pronounced at lower temperatures (20,21).…”

Section: Resultsmentioning

confidence: 78%

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Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Petitpas¹,

Bhattacharya²,

Twine³

et al. 2001

Journal of Biological Chemistry

777

605

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Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determined the crystal structures at 2.5 Å-resolution of HSA-myristate complexed with the R-(؉) and S-(؊) enantiomers of warfarin, a widely used anticoagulant that binds to the protein with high affinity. The structures confirm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein-drug interaction. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amino acid side chains at the binding site, thus accounting for the relative lack of stereospecificity of the HSA-warfarin interaction. The conformation of the warfarin binding pocket is significantly altered upon binding of fatty acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid.

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Section: Resultsmentioning

confidence: 78%

“…Warfarin (3-(␣-acetonylbenzyl)-4-hydroxycoumarin) binds to drug site I with high affinity (K d Ϸ 3 M) (13,20,21). A crystallographic study in 1992 confirmed subdomain IIA as the binding locus for a single molecule of warfarin but was unable to give specific details on the binding interactions because of the limited resolution of the data (10).…”

mentioning

confidence: 99%

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Petitpas¹,

Bhattacharya²,

Twine³

et al. 2001

Journal of Biological Chemistry

777

605

View full text Add to dashboard Cite

show abstract

“…According to Sudlow's nomenclature, bulky heterocyclic anions bind preferentially to Sudlow's site I (located in subdomain IIA), whereas Sudlow's site II (located in subdomain IIIA) is preferred by aromatic carboxylates with an extended conformation ( Fig. 1) [3,11,[18][19][20][21][22][23][24]. Among others, HSA is able to bind 7 equiv of long-chain fatty acids (FAs) at multiple binding sites (labeled FA1 to FA7) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

et al. 2011

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“…It can also cause gastrointestinal ulceration, hemorrhage, and inhibition of platelet aggregation 19,69,70 . Of the other non-steroidal anti-inflammatory drugs, flurbiprofen 71 , meclofenamate sodium 72 73,74 , piroxicam 75 , sulindac 76,77 , tiaprofenic acid 78 , tolmetin sodium 79 may potentiate the anticoagulant effect. In many cases the result of concomitant therapy was an increased prothrombin time which may or may not be clinically significant; in other cases haemorrhage occurred.…”

Section: Drugs Affecting Haemostasismentioning

confidence: 99%

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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Binding of Nonsteroidal Anti-Inflammatory Agents and Their Effect on Binding of Racemic Warfarin and Its Enantiomers to Human Serum Albumin

Cited by 62 publications

References 30 publications

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

Interactions of Warfarin

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