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

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.