Phenylbutazone displacement

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... 

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

Phenylbutazone displaces warfarin from binding sites on serum albumin, temporarily increasing its effects before the clearance of warfarin increases because of an increase in the unbound fraction (37). If that were the only mechanism, this interaction would not be important. However, phenylbutazone also inhibits the metabolism of 5-warfarin and induces the metabolism of -warfarin (38) the half-life of racemic warfarin is unchanged, but because the S isomer is more potent than the R isomer, the action of warfarin is potentiated (SED-9,144) (36,39). 

It s long been believed that problems can arise when a drug that binds to plasma proteins and reaches relatively high concentrations (say phenylbutazone) displaces another drug that s... 

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. 

Methotrexate clearance can be decreased by the coadministration of NSAIDs however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim. 

Drugs with high affinities for plasma albumin can also displace drugs with lower affinities. For example, sulfonamides bind to plasma proteins, but if phenylbutazone, which has a greater affinity for the binding sites, is administered, the concentration of the free sulfonamides in the plasma will increase due to drug displacement. 

Drugs may compete for binding sites on the plasma or tissue protein, or may displace previously bound drugs. For example, phenylbutazone may compete with phenytoin for binding to albumin. 

The drug with the higher affinity constant will successfully displace the drug with the lower. The result is an increase in the free drug concentration of the latter. For example, tolbutamide (an oral hypoglycemic agent used in maturity-onset diabetes mellitus) is approximately 95 percent bound and 5 percent free (see Table 4.1). In the presence of the anti-inflammatory drug phenylbutazone (which is nearly 100 percent... 

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. 

Pharmacokinetics Phenylbutazone is rapidly and completely absorbed after oral or rectal administration. Oxyphenbutazone is an active metabolite and contributes to the activity of the parent drug. Like most of the other NSAIDs, phenylbutazone is extensively bound to plasma proteins. This property causes displace-... 

Phenylbutazone Phenytoin Valproate Risk of toxicity, particularly with phenytoin altered relation between total concentration and effect Displacement from plasma protein binding sites and inhibition of metabolism of the affected drugs... 

Phenylbutazone Potentiation (213) Displacement from binding sites on plasma proteins stereoselective inhibition of metabolism (warfarin) causes peptic ulceration (214,215) Avoid concurrent use... 

Phenytoin Phenylbutazone Oxyphenbutazone Other NSAIDs Inhibition of metabolism of phenytoin, increasing plasma concentration and risk of toxicity Displacement of phenytoin from plasma albumin, reducing total concentration for the same unbound (active) concentration Avoid these NSAIDs if possible if not, intensive plasma concentration monitoring Careful interpretation of serum total phenytoin concentration measurement of unbound concentration can be helpful, if available... 

Phenylbutazone can displace sulfonamides from proteinbinding sites (SED-9,144) (45). 

Warden WM. Drug displacement from protein binding source of the sulphadoxine liberated by phenylbutazone. Br J Pharmacol 1971 43(2) 325-34. 

Phenylbutazone may displace the sulfonamides from plasma protein-binding sites, increasing... 

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