Plasma-Protein Binding Sites

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. 

Drug biotransformation usually converts the nonpolar active drugs into more water-soluble, but pharmacologically inactive, products. Drugs may stimulate or inhibit the metabolism of other drugs. These interactions may be either innocuous or detrimental to the expected therapeutic objectives. 

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for 

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Drug Interactions During Distribution Displacement from Plasma Protein Binding Sites... 

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. 

A) An adverse drug reaction may occur if warfarin is displaced from plasma protein binding sites. 

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. 

One of the most important practical aspects of protein binding is the fact that drugs of similar or markedly dissimilar structure may compete for the same binding sites on the protein (7). Hence, multidrug therapy may lead to alteration in the plasma concentration and the rate of elimination of drugs, because of multiple competition for the plasma protein-binding sites. 

Proximal tubular secretion is an energy-dependent active-transport mechanism. Specific high-affinity proteins in the proximal tubule transport drugs into the tubule for elimination via the urine. These proteins can also remove acidic and basic drugs from plasma protein-binding sites and transport them into the tubule. Since it is carrier-mediated, this mechanism is a saturable system. Therefore, other drugs may also compete for transport where similar carriers are employed. 

Once a toxic compound has been absorbed, the disposition of it in vivo may also be affected by the dose. Thus, saturation of plasma-protein binding sites may lead to a significant rise in the plasma concentration of free compound, with possible toxic effects. This, of course,... 

The suggested mechanism of this interaction was that finasteride inhibited the hepatic metabolism of sibutramine, which then displaced finasteride from its plasma protein binding sites inhibition of 5HT (serotonin) and noradrenaline reuptake by sibutramine then triggering the psychotic event. 

Iopanoic acid is as potent a uricosuric agent as probenecid and this effect might explain some renal complications aspirin reduces the uricosuric effect but can also impair X-ray visualization because of competition at plasma protein-binding sites. Fluctuations of serum urate after oral cholecystography can interfere with diagnostic tests and even precipitate an attack of gout (578). 

Salicylates Interference with renal excretion of drugs that undergo active tubular secretion. Salicylate renal excretion dependent on urinary pH when large doses of salicylate used. Aspirin (but not other salicylates) interferes with platelet function. Large doses of salicylates have intrinsic hypoglycemic activity. Salicylates may displace drugs from plasma protein binding sites. Carbonic anhydrase inhibitors [NE] Increased acetazolamide serum concentrations increased salicylate toxicity due to decreased blood pH. 

METHOTREXATE SULFAMETHOXAZOLE/ TRIMETHOPRIM t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Sulfamethoxazole displaces methotrexate from plasma protein-binding sites and also 1 renal elimination of methotrexate. Trimethoprim inhibits dihydrofolate reductase, which leads to additive toxic effects of methotrexate Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasias and liver, renal and pulmonary toxicity... 

Drugs may interact competitively at plasma protein binding sites as is discussed on page 131. 

The poison should dissociate readily from any plasma protein binding sites... 

The action of sulphonylureas is intensified by heavy sulphonamide dosage and some sulphonamides increase free tolbutamide concentrations, probably by competing for plasma protein binding sites. These examples suffice to show that the possibility of interactions of practical clinical importance is a real one. 

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... 

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