Related Experiment Video
Updated: Jun 11, 2026

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
An improved nonlinear model describing the hepatic pharmacokinetics of digoxin: evidence for two functionally
Michael Weiss1, Peng Li, Michael S Roberts
1Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany. michael.weiss@medizin.uni-halle.de
Purpose:
To develop a semi-distributed liver model for the evaluation of saturable sinusoidal uptake and binding kinetics of the Oatp1a4 substrate digoxin.
Methods:
In the perfused rat liver, two successive digoxin doses of 42 and 125 microg were administered, and the outflow concentration was determined by LC/MS/MS. [14C]-sucrose was used as vascular reference. The data were analyzed simultaneously by a population approach using sucrose to determine the sinusoidal mixing of digoxin.
Results:
The results suggest the existence of a high-affinity, low-capacity system, and a low-affinity, high-capacity system for sinusoidal uptake with apparent Michaelis constants (K(M)) of 0.24 and 332 microg/ml, respectively. Incorporation of saturable sinusoidal binding of digoxin considerably improved the fit, and the parameter estimates were consistent with those of binding to hepatic Na,K-ATPase. Simpler models that neglect the concentration gradient in flow direction failed to describe the outflow data in the high dose range.
Conclusion:
The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.
Related Concept Videos
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
A recent model describes pravastatin's hepatobiliary excretion, mediated...
Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
Pharmacodynamic Models: Link Model and Systems Pharmacodynamic Model
Physiological Pharmacokinetic Models: Blood Flow-Limited Versus Diffusion-Limited Models
Drug Distribution as One-Compartment Model and Elimination by Nonlinear Pharmacokinetics: Overview
For instance, consider the metabolism of sodium salicylate. This compound is metabolized into two distinct substances: a glucuronide and a glycine conjugate. The rate of conjugation depends on...
Nonlinear Pharmacokinetics: Overview
Nonlinearity can arise due to the saturation of plasma protein-binding or...