Plasma protein binding interactions

Rolan PE. Plasma protein binding interactions - why are they stiU regarded as clinically important . Br J Clin Pharmacol 1994 37 125-8. 

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. 

Dicoumarol appears to increase the effects of tolbutamide by inhibiting its metabolism by the liver. This may also be true for chlorpropantide. The increase in the anticoagulant effects of dicoumarol by tolbutamide may, in part, be due to a plasma protein binding interaction. In the case of phenprocoumon there seem to be several different mutually opposing processes going on, which cancel each other out. There is no clear explanation for most of these interactions. 

Grimaldi R, Lecchini S, Crema F, Perucca E. In vivo plasma protein binding interaction between valproic acid and naproxen. EurJ Drug Metab Pharmacokinet (1984) 9, 359-63. 

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

Additional assays used in early pharmaceutical property profiles usually include plasma protein binding, individual cytochrome P450 assays, stability in the presence of serum, production of metabolites likely to be involved in covalent binding to biomolecules, and interaction with efflux pumps ... 

Plasma contains a large variety of proteins, all of which have the potential to interact with drugs. Albumin is generally considered to be the most important contributor to the plasma protein binding of drugs (GIO, Gil, M16), but for some, e.g., steroids, other proteins play a major role. 

Impact of Plasma Protein Binding on PK, Exposure, Safety Margins, Potency Screens and Drug-Drug Interaction... 

Rolan, P.E. (1994) Plasma protein binding displacement interactions-why are they still regarded as clinically important British Journal of Clinical Pharmacology,... 

Christensen, H., Baker, M., Tucker, G.T. and Rostami-Hodjegan, A. (2006) Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data. Journal of Pharmaceutical Sciences, 95, 2778-2787. 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

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

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