New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition

Sammanfattning

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

Nyckelord

drug disposition; drug-target interaction; multi-drug target binding; multi-target drug disposition

Publicerad i

AAPS Journal
2018, Volym: 20, nummer: 4, artikelnummer: 69Utgivare: SPRINGER

SLU författare

• Gabrielsson, Johan

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Farmakologi och toxikologi


Publikationens identifierare

DOI: https://doi.org/10.1208/s12248-018-0221-x

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/95649