Plasma protein binding interactions concentration

Plasma protein binding interactions are usually clinically unimportant, but they should be recognized, because they alter the relation between serum drug concentration and the clinical response if displacement occurs, therapeutic and toxic effects are reached at a total drug concentration lower than usual. For example, valproic acid and salicylate displace phenytoin from plasma proteins this usually results in a fall in total phenytoin concentration without any change in the concentration of unbound (pharmacologically active) phenytoin. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

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. 

Diaminopyrimidines are weak bases. Peak plasma concentrations are reached early and diaminopyrimidines are soon found in high concentrations in tissues. In fact, the tissue concentrations are often higher than the concentrations in serum. When inflammation is present, trimethoprim levels in the CSF may reach 50% of the plasma concentrations. CSF concentrations of pyrimethamine are 25-50% of the plasma concentrations. The Vd for trimethoprim and pyrimethamine is 1.51/kg in horses. The protein binding of trimethoprim is moderate (50%). There is no protein-binding interaction between the sulfonamides and the diaminopyrimidines. 

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