On the Possibility of Self-Induction of Drug Protein Binding

Free drug percentage of moxidectin declines with increasing concentrations in the serum of marsupials

“…The atypical pattern of increased protein binding as drug concentrations increase has been described previously, being largely attributed to the drug changing the conformation of the protein and enhancing drug binding to another site on the protein ( Levy and Nagashima, 1969 ; Altmayer, 1995 ; Berezhkovskiy, 2010 ). This concept has been well studied in albumin, which undergoes structural changes after ligand binding, where the conformation changes of the protein due to exogenous or endogenous binding can either increase or decrease drug-binding capacity ( Sudlow et al, 1975 ).…”

A Convenient Method to Measure Blood–Plasma Concentration Ratio Using Routine Plasma Collection in In Vivo Pharmacokinetic Studies

“…[6][7][8] The blood cell-plasma partition coefficient p (Eq. 2) is also considered as concentration independent because the plasma concentrations of compounds are relatively low.…”

The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

“…The authors concluded that location of the interaction is the primary factor that determines its magnitude: liver usually contributes more than the kidneys, while interactions at other locations, such as the BBB, usually have limited effect on volume of drug distribution. Concentration-dependent drug distribution can also originate from nonlinear plasma protein binding (e.g., due to self-induction of drug--protein binding due to two-step mechanism of drug protein binding with binding at the first site leading to activation of the second binding site, as suggested recently for propofol, indomethacin, lidocaine and other drugs by Berezhkovskiy [49]) that can lead to significant, clinically-relevant changes in plasma drug protein binding in patients with decreased plasma protein concentrations (e.g., due to uremia, hepatic diseases, epilepsy). It should be noted that the Øie--Tozer model can be applied for analysis of drug distribution in conditions of constant magnitude of nonlinear process, that is, steady-state conditions with constant extent of saturable tissue or protein binding, drug--drug interactions for transporter-mediated transport and so on.…”