Plasma protein-binding sites, interactions

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

Table 1.7.2 Interactions caused by displacement of drugs from plasma protein binding sites.

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. 

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

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. 

Interaction seen only with phenytoin and mediated by displacement from plasma protein binding sites no reduction in methotrexate activity is expected the relation between total methotrexate concentration and effect can be altered. 

Drug interactions with sulfonylureas and biguanides are common non-steroidal antiinflammatory drugs, warfarin, alcohol, monoamine oxidase inhibitors, some uricosurics, some antibacterials and some antifungals can interact with them. All increase the risk of hypoglycaemia. The mechanism is probably competition for metabolizing enzymes or displacement from plasma protein binding sites. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

Toxicity The toxic effects of sulfonamides include skin rashes, gastrointestinal distress, hemolysis, kidney damage, and drug interactions caused by competition for plasma protein binding sites. Pyrimethamine may cause folic acid deficiency when used in high doses. 

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. 

The most likely explanation is that azapropazone inhibits the liver enzymes concerned with the metabolism of phenytoin, resulting in its accumulation. It also seems possible that azapropazone displaces phenytoin from its plasma protein binding sites so that levels of unbound (and active) phenytoin are increased. Information seems to be limited to the reports cited, but it appears to be a clinically important interaction. The incidence is uncertain, but an interaction occurred in all 5 of the subjects in the study cited. The manufacturers contraindicate azapropazone in patients taking phenytoin. ... 

Some lists, reviews and books on interactions say that chloramphenicol, aminosalieylie aeid, sodium salieylate, sulfamethoxypyridazine, tetracycline or tolbutamide interact with methotrexate, apparently based largely on the preliminary findings of a study in which male mice were treated for 5 days with each of 4 doses of methotrexate (1.53 to 12.25 mg/kg intravenously) and immediately afterwards with non-toxic intraperitoneal doses of the drugs listed. These drugs were said to decrease the lethal dose and/or decrease the survival time of the mice That is to say, the toxicity of the methotrexate was increased. The reasons are not understood, but it is suggested that displacement of the methotrexate from its plasma protein binding sites could result in a rise in the levels of unbound and active methotrexate, and in the case of sodium salicylate to a decrease in renal clearance. 

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