Phenylbutazone plasma protein binding

Phenylbutazone is metabolized by the liver at a rate of about 15-25% per day (B33), but plasma levels do not increase proportionately with increasing doses of the drug. The work of Burns et al. (B33) indicates that above a certain level plasma phenylbutazone concentrations plateau. The concentration at which this occurs varies among individuals and is probably a reflection of the level at which saturation of high-affinity plasma protein binding sites occurs. 

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. 

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

Phenylbutazone very effectively displaces the anticoagulants from their plasma protein binding sites, thereby increasing the concentrations of free and active anticoagulant (an effect easily demonstrated in By... 

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. 

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. 

The peak plasma concentration is reached 2 h after oral administration. The degree of binding of phenylbutazone to plasma proteins is 98%. The long elimination half-life of phenylbutazone (mean -70 h) exhibits large interindividual and intraindividual variation. It is metabolized in the liver by oxidation and glucuronidation and excreted in the urine and to a lower degree (-25%) in the faeces (Aarbakke, 1978). Oxyphenbutazone is an active metabolite of phenylbutazone. The metabolic pathway of phenylbutazone is shown in Scheme 72. 

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

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

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