Gabrielsson, Johan
- Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
Sammanfattning
In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved. Understanding target turnover is pivotal for optimising these processes when target-mediated drug disposition (TMDD) prevails. By a combination of mathematical analysis and simulations, we also show that the evolution of the three concentration profiles towards their respective steady-states can be quite complex, especially for lower infusion rates. We also show how parameter estimates obtained from iv bolus studies can be used to derive steady-state concentrations of ligand, target and complex. The latter may serve as a template for future experimental designs.
Nyckelord
constant-rate infusion protocol; drug disposition; drug-target interaction
Publicerad i
AAPS Journal
2017, volym: 19, nummer: 3, sidor: 772-786
Utgivare: SPRINGER
SLU författare
UKÄ forskningsämne
Farmakologi och toxikologi
Publikationens identifierare
- DOI: https://doi.org/10.1208/s12248-016-0031-y
Permanent länk till denna sida (URI)
https://res.slu.se/id/publ/82806