An Improved Nonlinear Model Describing the Hepatic Pharmacokinetics of Digoxin: Evidence for Two Functionally Different Uptake Systems and Saturable Binding

Abstract

The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.

Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application ofmdr1aknockout (−/−) rats into absorption study of multiple transporter substrate

“…Based on these data, the renal clearance of digoxin was not taken in account to estimate the F h in this study in rats, due to the low impact on the CL tot . It is also proven that a transporter-mediated uptake process is a determinative step in the liver distribution in rats (Sun et al, 2004;Weiss et al, 2010); however, the F h was not influenced by pretreatment with quinidine. Conclusively, it was unlikely that the assessment of digoxin absorption was affected by the inhibition of hepatic and renal eliminations by quinidine.…”

“…Oatp1a4, which is expressed in the brain and liver of rodents, in addition to P-gp, appears to play a significant role in the pharmacokinetics of digoxin (Gao et al, 1999;Lam & Benet, 2004;Weiss et al, 2010). The mRNA expression of various oatp family members (Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b1 and Oatp4a1) has been reported in the rat intestine (Augustine et al, 2005;Koitabashi et al, 2006;Walters et al, 2000).…”

“…The main clearance mechanism is hepatic metabolism via the formation of digoxigenin bis-digitoxoside mediated by cytochrome P450 3A (CYP3A; Salphati & Benet, 1999) and urinary excretion of digoxin was marginal in rats (Funakoshi et al, 2005), which is different from humans, who mainly show renal excretion of the unchanged form (Pedersen et al, 1981). Kinetic analysis using a detailed compartment model describing the sinusoidal concentration gradient in the liver indicates that digoxin is distributed to the liver via an uptake system with high and low affinity components in rats (Weiss et al, 2010). The detailed tissue distribution profile of digoxin in mice is investigated using mdr1a knockout [mdr1a (À/À)] mice in combination with quinidine, a P-gp inhibitor (Fromm et al, 1999).…”

Drug structure–transport relationships

“…My group has moved, influenced by Michael Weiss, to using an empirical dual inverse Gaussian function that best describes the outflow profiles after bolus injections into the liver [94] combined with a two compartment model that enables the relative importance of permeability, diffusion and binding in the cells to be dissected out [95]. With Yuri Anissimov, we have also developed a compartmental model for hepatic elimination that accurately describes the observed vascular dispersion [96], but our application of this model has, to this stage been limited [97]. …”

Multiphoton microscopy and fluorescence lifetime imaging provide a novel method in studying drug distribution and metabolism in the rat liver in vivo

“…1 A limitation in these models is the "black box" nature of the experiments, in which physiological pharmacokinetic models are used to deduce events occurring in the organs using the observed outflow profiles. [3][4][5][6] We have sought to improve on this modeling by building an in silico liver that consists of a collection of flexible, hepatomimetic, in silico "cells" which are, in turn, assembled together into hepatic "lobules" and using outflow profiles to validate the predicted drug disposition in the liver. 7,8 A much more precise method of analyzing pharmacokinetic events in the liver is to directly observe them.…”