Pharmacokinetics drug-protein interactions

MacKichan, J.J. (1989) Protein binding drug displacement interactions—fact or fiction Clin Pharmacokinet 16 65-73. 

Pharmacokinetics. Warfarin is readily absorbed from the gastrointestinal tract and like all the oral anticoagulants, is more than 90% bound to plasma proteins. Its action is terminated by metabolism in the liver. Warfarin (t/ 36 h) is a racemic mixture of approximately equal amounts of two isomers S (t)/ 35 h) and R 50 h) warfarin, i.e. it is in effect two drugs. S warfarin is four times more potent than R warfarin. Drugs which interact with warfarin affect these isomers differently. 

Protein interactions have been investigated by ITP (D6). It has, for example, been possible to determine the number of sodium dodecyl sulfate (SDS) molecules bound to bovine serum albumin (H14, H15) and to investigate the binding of drugs such as indomethacin to human serum albumin (H15). This method could be of value in pharmacokinetic studies. 

Xia CQ, Yang JJ, Gan L-S. Breast cancer resistance protein in pharmacokinetics and drug-dmg interactions. Expert Opin Drug Metab Toxicol 2005b l 595-611. 

Its duration of action is 60-120 minutes, depending on the vascularity of the site blocked as well as added adjuvants such as epinephrine. The drug is 70% protein-bound, with 30% in the free unbound form. It is this 30% that is rapidly cleared by the systemic circulation for hepatic metabolism. The vasoconstrictive properties of epinephrine help to decrease this systemic uptake of the drug and thus to prolong its duration of action. Other adjuvants such as the alpha-2 receptor agonists clonidine and dexmedetomidine have been studied recently and found to prolong the duration of action of lidocaine. Their mechanism of action (specific receptor vs. pharmacokinetic/phar-macodynamic interaction with local anesthetics) and site (central vs. peripheral) of action have not been fully elucidated [6-8]. 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Drug Levels in Plasma. Drug levels may also be measured in a clinical trial. Such levels are usually part of a pharmacokinetic analysis but also provide important safety data. This information would be particularly relevant in cases of suspected or actual drug overdosage, drug interactions, to correlate medicine levels with toxic events, or in other situations. It must be clarified whether free levels of the drug and/or the protein bound will be measured by the laboratory. 

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