Impact of protein binding on receptor occupancy: a two-compartment model.
In this paper we analyse the impact of protein-, 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 time-curves 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.
Peletier
Lambertus A
LA
Mathematical Institute, Leiden University, Leiden, The Netherlands. peletier@math.leidenuniv.nl
Benson
Neil
N
van der Graaf
Piet H
PH
D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D004333:Drug Administration Routes; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism; D013997:Time Factors
D004364:Pharmaceutical Preparations; D011956:Receptors, Cell Surface; D011955:Receptors, Drug