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

Abstract:

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.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Weiss M,Li P,Roberts MS

doi

10.1007/s11095-010-0204-9

subject

Has Abstract

pub_date

2010-09-01 00:00:00

pages

1999-2007

issue

9

eissn

0724-8741

issn

1573-904X

journal_volume

27

pub_type

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