Protein binding, drug interactions

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. 

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

MacKichan JJ. Protein binding drug displacement interactions fact or fiction Clin Pharmacokinei 1989 16 65-73. 

Drugs may affect the absorption, distribution, metabolism, or excretion of other drugs. This includes those interactions in which the gastrointestinal absorption of a drug, plasma protein binding, drug metabolism, and urinary excretion are either enhanced or inhibited. 

Rosenthal AE (1967) A graphic method for the determination and presentation of binding parameters in a complex system. Analytical Biochemistry 20 525-532 Sansom LN, Evans AM (1995) What is the True Clinical Significance of Plasma Protein Binding Displacement Interactions Drug Safety 12(4) 227—233 Scatchard G (1949) The attractions of protein for small molecules and ions. New York Academic of Sciences 51 660-692... 

In vitro target specificity CeU-free assays CeU assays Protein binding Drug-drug interaction Metabolic stability CeU-based toxicity Membrane permeability... 

Sansom LN, Evans AM. What is the true clinical significance of plasma protein binding displacement interactions Drug Saf 1995 12 227-33. 

Effective orally and eliminated via hepatic metabolism (acetylation) and renally as unchanged drug. Less water-soluble metabolites may cause crystalluria. Bind to plasma proteins —>T drug interactions including T effects of methotrexate, phenytofn, and warfarin. 

This means that overall exposure to unbound drug can t be affected by plasma binding or plasma protein binding displacement interactions. Furthermore, if the drug is a high hepatic extraction-ratio drug, such that CLint >Qj then Q hepatic blood flow rate, becomes limiting, and Equation (12.31) becomes ... 

Table 16.8 Transient effects on free drug concentrations after a protein-binding displacement interaction results in an increase in free fraction ...

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

Alternatively, one interesting drug delivery technique exploits the active transport of certain naturally-occurring and relatively small biomacromolecules across the cellular membrane. For instance, the nuclear transcription activator protein (Tat) from HIV type 1 (HlV-1) is a 101-amino acid protein that must interact with a 59-base RNA stem-loop structure, called the traus-activation region (Tar) at the 5 end of all nascent HlV-1 mRNA molecules, in order for the vims to replicate. HIV-Tat is actively transported across the cell membrane, and localizes to the nucleus [28]. It has been found that the arginine-rich Tar-binding region of the Tat protein, residues 49-57 (Tat+9 57), is primarily responsible for this translocation activity [29]. 

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