The impact of the concentration of drug binding plasma proteins on drug distribution according to Øie-Tozer’s model

Abstract

1. New equations have been developed from an updated version of Øie-Tozer's model expressing how the free concentration and volume of distribution change in relation to changes in the concentration of drug binding plasma proteins. This updated model accommodates more than one drug binding plasma protein to contribute to the plasma protein binding. 2. Demonstrations of the model show that variability in the concentration of one plasma protein has considerably less impact on the free drug concentration and volume of distribution if other plasma proteins contribute to binding, than if they don't.

Physiologic Targets and Modes of Action for CBL0137, a Lead for Human African Trypanosomiasis Drug Development

“…A "physiologic target of a drug" may be defined as a macromolecule whose knockdown or over-expression produces identical (or very similar) molecular effects as treatment of cells with the drug (Mensa-Wilmot, 2021). Many drug-binding proteins [for example, plasma proteins (Berezhkovskiy, 2008;Cho et al, 2010;Svennebring, 2016)] are not physiologic targets of the small molecules.…”

How Physiological Targets Can Be Distinguished from Drug-binding Proteins

“…Many drug-binding proteins may not be the physiological targets. For example, plasma proteins bind to drugs (Berezhkovskiy, 2008;Cho et al, 2010;Svennebring, 2016) but are not considered physiological targets of the small molecules.…”

Measuring and Using Free Drug Concentrations: Has There Been ‘Real’ Progress?

“…If free drug concentrations correlate with therapeutic effects better than total concentrations, as has been shown in numerous studies [1][2][3][4], why have they not been adopted more widely? The main reasons could be grouped in three categories: analytical, therapeutic and availability of funding for research.…”

“…During early drug discovery, protein binding is usually determined using affinity chromatography and is subsequently used in preliminary human trials in order to achieve efficient free concentrations at the targeted area [10]. The unbound drug concentrations and drug-target binding kinetics are also key parameters in formulating differential equations for PK-PD modeling of in vivo activity, drug-drug interactions, influence of plasma protein binding on the volume of distribution and target-mediated drug disposition [4,11,12]. Free concentrations of antibiotics and antiepileptic drugs have long been known to be important for therapeutic effects, and the evidence keeps accumulating.…”