Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na+/K+ ATPase digoxin binding

Li, Peng, Weiss, Michael and Roberts, Michael S. (2012) Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na+/K+ ATPase digoxin binding. European Journal of Pharmaceutical Sciences, 47 2: 506-511. doi:10.1016/j.ejps.2012.07.008


Author Li, Peng
Weiss, Michael
Roberts, Michael S.
Title Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na+/K+ ATPase digoxin binding
Formatted title
Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na+/K+ ATPase digoxin binding
Journal name European Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 0928-0987
1879-0720
Publication date 2012-09
Sub-type Article (original research)
DOI 10.1016/j.ejps.2012.07.008
Volume 47
Issue 2
Start page 506
End page 511
Total pages 6
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Collection year 2013
Language eng
Abstract The mechanism by which quinidine affects hepatic digoxin pharmacokinetics remains controversial. Here, we study the role of displacement of digoxin from hepatic sinusoidal binding sites by quinidine. We used the impulse–response technique in the single-pass perfused rat liver to describe the digoxin hepatic disposition by a physiologically-based pharmacokinetic liver model. The impulse–response study involved analysis of outflow curves following two consecutive doses of digoxin (42 and 125 μg) without and with quinidine (10 μM) in perfusate. In addition, the effect of quinidine on digoxin binding in liver subcellular fractions was quantified. Quinidine increased the peak outflow concentration for digoxin at the low digoxin dose but not at the high dose. This increase could be adequately described when digoxin displacement from sinusoidal and intrahepatic binding sites was included in the model. Inhibition of digoxin binding by quinidine was also observed in vitro. The decrease of biliary excretion of digoxin by quinidine was accompanied by a linear increase in sinusoidal efflux of digoxin’s primary metabolite, digoxigenin bisdigitoxoside (Dg2). In contrast to biliary excretion, inhibition of sinusoidal uptake may become dominant only for high concentrations of quinidine.
Keyword Perfused rat liver
Digoxin binding
Quinidine
Interaction
Pharmacokinetic model
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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