NSAIDs protein binding

NSAID Bioavailability (%) Half-life (hours) Peak (hours) Protein binding (%) Renal elimination (%) ... 

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... 

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. 

Mecfianism of Action An NSAID that inhibits prostaglandin synthesis, reducing the inflammatory response and the intensity of pain stimuli reaching the sensory nerve endings. Therapeutic Effect Produces analgesic and anti-inflammatory effects. Pharmacokinetics Rapidly and completely absorbed from the G1 tract. Food delays absorption of salsalate. Protein binding Fligh (to albumin). Metabolized in the liver. Excreted in urine. Removed by hemodialysis. Half-life 1 hr. 

As the protein binding of most NSAIDs is very high, raised bilirubin and/or low albumin levels could increase the free fraction of NSAIDs available for pharmacological activity. 

Concomitant use of heparin and oral anticoagulants can increase the risk for bleeding due to the antiplatelet effect of aspirin. In addition, use with alcohol can increase the risk of Gl bleeding. / spirin displaces a number of drugs (e.g., tolbutamide, nonsteroidal anti-inflammatory drugs [NSAIDs], methotrexate, phenytoin, and probenecid) from protein binding sites in the blood. Corticosteroid use can reduce serum salicylate levels by increasing the clearance of aspirin. 

Another characteristic pharmacokinetic parameter shared by many NSAIDs is a small apparent volume of distribution (Vj). For many NSAIDs the Vd is often <0.21/kg (Landoni Lees 1995b, Owens et al 1995a). This small is, at least partially, a direct result of the high degree of plasma protein binding typical of most NSAIDs. 

Roughly 80-90% of the salicylate in plasma is bound to proteins, especially albumin, at concentrations encountered clinically the proportion of the total that is bound declines as plasma concentrations increase. Hypoalbuminemia, as may occur in rheumatoid arthritis, is associated with a proportionately higher level of free salicylate in the plasma. Salicylate competes with a variety of compounds for plasma protein binding sites these include thyroxine, triiodothyronine, penicillin, phenytoin, sulfinpyrazone, bilirubin, uric acid, and other NSAIDs such as naproxen. 

Children given antipyretic doses of aspirin co-administered with valproate were found to exhibit a decrease in protein binding and an inhibition of the metabolism of valproate. The common use of aspirin should alert to the need for caution if these drugs are co-administered. Interaction with other non-steroidal anti-inflammatory drugs (NSAIDs) may not be so prominent. 

The in vitro plasma protein binding has been reported to be stereoselective for many NSAIDs such as ibuprofen, flurbiprofen, ketoprofen, and etodolac (Table 3) [261-265]. Ibuprofen protein binding is stereoselective and nonlinear within the therapeutic concentration range (1 to 50mg/L) [259]. The S enantiomer reportedly has a higher unbound fraction than antipode in human plasma [261,266]. An apparent decrease in the... 

Aspirin and the NSAIDs generally undergo few clinically significant pharmacokinetic interactions. The majority are highly protein bound, and have the potential to interact with other drugs via this mechanism. However, with a few exceptions, most of these interactions are not clinically important (see Protein-binding interactions , (p.3)). 

The damaging effects of aspirin and NSAIDs on the gut appear to be additive. The mechanisms behind the pharmacokinetic changes have not been resolved. Changes in the rates of absorption and renal clearance and competition for plasma protein binding have been proposed. 

Uncertain. Mefenamic acid can displace warfarin from its plasma protein binding sites, and in vitro studies have shown that therapeutic concentrations (equivalent to 4 g daily) can increase the unhound and active warfarin concentrations by 140 to 340%, but this interaction mechanism alone is only likely to have a transient eifect. See also Coumarins and related drugs + NSAIDs , p.427. 

Drug interactions like other NSAIDs, plasma protein binding of ketorolac is extensive, leading to potential drug interactions due to displacement of other highly protein-bound drugs. Concurrent use of probenicid with ketorolac will decrease its elimination. Concurrent use of furosemide with ketorolac will decrease the diuretic s effect. Concurrent administration of other NSAIDs may increase plasma levels of ketorolac. 

Distribution. The NSAIDs are highly protcin-lioimil, so agents that displace them from protein-binding sites (e.g., sulfonamiries) may enhaiice ih r toxicity. 

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