Impact of protein binding on receptor occupancy: A two-compartment model

Abstract

In this paper we analyse the impact of protein-and lipid-and receptor-binding on receptor occupancy in a two-compartment system, with proteins in both compartments and lipids and receptors in the peripheral compartment only. We do this for two manners of drug administration: a bolus administration and a constant rate infusion, both into the central compartment. We derive explicit approximations for the timecurves of the different compounds valid for a wide range of realistic values of rate constants and initial concentrations of proteins, lipids, receptors and the drug. These approximations are used to obtain both qualitative and quantitative insight into such critical properties as the distribution of the drug over the two compartments, the maximum receptor occupancy and the area under the drug-receptor complex curve. In particular we focus on assessing the impact of the dissociation constants, K P , K L and K R of the drug with, respectively, the proteins, the lipids and the receptors, the permeability and the surface area of the membrane between compartments, and the rate the drug is eliminated from the system.

Impact of saturable distribution in compartmental PK models: dynamics and practical use

“…In analysing these models subject to the conditions ( 46 – 49 ) listed in Methods, a mathematical framework has been created which can be used to analyse comparable models, which involve additional processes such as (i) leakage, or (ii) binding of the ligand to proteins, lipids and receptors in the central or the peripheral compartment, such as discussed in [ 9 ], or (iii) when the model involves additional compartments. This analytical machinery makes it possible to give quantitative estimates of the impact of these processes on the drug distribution between compartments and over time.…”

Coping with time scales in disease systems analysis: application to bone remodeling

“…Thus, after a brief initial period, x ( τ ) and z ( τ ) are to good approximation related by the equation i.e., x and z are in quasi - equilibrium or quasi - steady state . For more details of this “quasi-steady state approximation” we refer to [6, 7, 19, 20]. …”

“…Such reduced models yield dynamic properties that are very similar to those of completely mechanistic models but require the identification of fewer parameters. They also yield important insights into the impact of different parameters on the full system and often explicit expressions and quantitative estimates for drug-, system-, and/or disease-specific characteristics, such as clearance or the area under the curve of different compounds [6, 7]. …”

Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

“… The concentration profile of the free drug in plasma and at the target site (pharmacokinetics, rebinding) [26,100]  Non-specific binding in plasma and target tissue [101]  The concentration of the target [26]  Competition between drug and endogenous ligand binding [14,15]  Target turnover [23], [102]  Signal transduction [103] These factors can all influence the ultimate importance of drug-target binding kinetics, thus putting the binding kinetics in the in vivo context. Therefore, these factors need to be taken into account in the translation from in vitro to in vivo target binding [104].…”