An improved nonlinear model describing the hepatic pharmacokinetics of digoxin: evidence for two functionally different uptake systems and saturable binding.
OBJECTIVE
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.


CONCLUSIONS
The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.
Weiss
Michael
M
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany. michael.weiss@medizin.uni-halle.de
Li
Peng
P
Roberts
Michael S
MS
D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D017711:Nonlinear Dynamics; D027361:Organic Anion Transporters / Q000378:metabolism*; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013379:Substrate Specificity; D014018:Tissue Distribution
D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase