Phenylbutazone Warfarin

Choiestyramine Warfarin, phenylbutazone, digitoxin, cephalexin and chlorothiazide Decreased absorption... 

Figure 8. Inhibition curves for warfarin, phenylbutazone, indomethacin, and palmitate at 25°C and pH 7.4 in 0.03M triethanolamine/HCl and...

Correct choice = A. Rifampin induces the hepatic mixed function oxidases that metabolize warfarin. Platelet inhibitors, such as aspirin, increase the anticoagulant effect of warfarin. Phenylbutazone can transiently increase the level of free warfarin by displacing it from the plasma albumin binding site. Cimetidine inhibits warfarin metabolism and causes potentiation of the anticoagulant. Disulfiram inhibits warfarin metabolism. 

Acenocoumarol, amiodarone, celecoxib, coumadin, dexamethasone, diclofenac, etoposide, fluconazole, fluoxetine, fluvas-tatin, fluvoxamine, ghmepiride, ghpizide, glyburide, ibuprofen, irbesartan, isoniazid, losartan, midazolam, phenylbutazone, phenytoin, rifampin, teniposide, tenoxicam, thiotepa, tolbutamide, torsemide, vitamin D, warfarin... 

Competition between drugs for plasma binding sites occurs and is responsible for some of the clinically most important changes in drug distribution. Phenylbutazone and oxyphenbutazone, for example, potentiate the action of warfarin by displacement (A2) and trichloroacetic acid, a major metabolite of chloral hydrate has a similar effect (S12) and is the cause of hemorrhagic complications during coumarin therapy (A2). 

Kraak et al. (38) reported the first ACE application to study drug binding to a plasma protein. They used the model system warfarin-human serum albumin (HSA) to compare the suitability of the Hummel-Dreyer, frontal analysis, and vacancy peak methods. A more methodologically intended paper from Erim and Kraak (39) used VACE to study the displacement of warfarin from bovine serum albumin (BSA) by furosemide and phenylbutazone. They concluded that VACE is especially suited to examining competitive properties of simultaneously administered compounds toward a given protein-drug system. 

Phenylbutazone was recognised to potentiate the anticoagulant effect of warfarin as long ago as 1959. As subsequent in vitro studies confirmed that phenylbutazone displaced warfarin from its protein binding site, it was assumed that any non-steroidal antiinflammatory drug (NSAID) would enhance warfarin s anticoagulant effect in this way. However it is now known that the interaction is due instead to a stereoselective inhibition of the metabolism of warfarin. Warfarin is available as a racemic mixture of two enantiomers R and S), and of these the S enantiomer is five times more potent as an anticoagulant. Phenylbutazone inhibits the metabolism of the... 

Methylphenidate may decrease therapeutic effects of concomitantly administered antihypertensive medications and may potentiate effects of warfarin, phenytoin, phenylbutazone, and tricyclic antidepressants. When methylphenidate and MAOIs are coadministered, hypertensive crisis may result. 

The most important drug interaction caused by displacement from plasma proteins occur with coumarin anticoagulants. Phenylbutazone displaces warfarin from its... 

Drugs like salicylates, dipyridamole, phenylbutazone decrease the ability of platelets to aggregate, and thus impairing the haemostasis if warfarin induced bleeding occurs. 

Acetanilide, propranolol, phenobarbital, phenytoin, phenylbutazone, amphetamine, warfarin, 17(x-ethinyl estradiol, naphthalene, benzpyrene... 

The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and... 

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, and ascorbic acid. Any additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors. 

Warfarin antagonists include vitamin K, barbiturates, glutethimide. rifampin, and cholestyramine. Warfarin potentiators include phenylbutazone. oxyphenbutazone, anabolic steroids, clofibrate, aspirin, hepatotoxins, disnlfirain, and metronidazole. In patients undergoing anticoagulation therapy with warfann, it has been found that cimetidine (used in therapy of duodenal ulcer) may increase anticoagulant blood levels and consequently prolong the prothrombin time. 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

Apart from being a diffusional barrier, mucin can also interact with drugs to decrease their bioavailability, as has been shown with tetracycline [106], phenylbutazone, and warfarin [107]. On the other hand, studies in rats showed that binding of some water-soluble drugs to intestinal mucus was essential for their absorption and that damage to the mucus significantly reduced absorption [108], The acidic mucus is essential for lipid absorption and could be important for the diffusion of lipophilic drugs (see below). 

Barry, B.W., and M.P. Braybrooks. 1975. Proceedings Influence of a mucin model system upon the bioavailability of phenylbutazone and warfarin sodium from the small intestine. J Pharm Pharmacol 27(Suppl. 2) 74P. 

Organochlorine insecticides are also well-known inducers. Treatment of rats with either DDT or chlordane, for example, will decrease hexobarbital sleeping time and offer protection from the toxic effect of warfarin. Persons exposed to DDT and lindane metabolized antipyrine twice as fast as a group not exposed, whereas those exposed to DDT alone had a reduced half-life for phenylbutazone and increased excretion of 6-hydroxy cortisol. 

Albumin has two binding sites Site I binds structurally unrelated substances (e.g., warfarin, phenytoin, and sulfonamides), and Site II, which is more selective, binds a smaller number of drugs (i.e., diazepam, phenylbutazone, and ibuprofen). 

Banfield C, O Reilly RE, Chan E, et al. Phenylbutazone-warfarin interaction in man further stereochemical and metabolic considerations. Br J Clin Pharmacol 1983 16 669-675. 

Figure 9. Inhibition of the reaction between p-nitrophenyl acetate and HSA by phenylbutazone and by phenylbutazone plus warfarin. Increasing amounts of phenylbutazone were added to a solution of HSA as described in Figure 8(0) and after the addition of 10 4M warfarin (M).

Figure 9 shows the effects of warfarin on the inhibition by phenylbutazone and Figure 10 shows the effects of phenylbutazone on the inhibition by warfarin. The presence of either at equal concentration with HSA eliminates the plateau otherwise observed in the inhibition curve of the other. These results clearly seem to indicate a common noninhibitory site for these compounds. Thus the high-affinity binding site (the noninhibitory site) and the secondary binding site (the inhibitory site) for these compounds are the same. 

Warfarin, Indomethacin, and Phenylbutazone—these compounds share a single high-affinity site that differs from those described above. They share a secondary site that is identical to or overlaps with that for tryptophan as described above. Salicylate—two primary binding sites. One is identical to or overlaps the tryptophan binding site and the other is identical to or overlaps the high-affinity site for warfarin, indomethacin, and phenylbutazone as described above. 

---