Tissue binding sites involved in quinidine-cardiac glycoside interactions

Quinidine has been shown to alter pharmacokinetics of digoxin by displacing the glycoside from mutual binding sites which are stereospecific with respect to quinidine. Characteristics of the binding site involved in quinidine-digoxin interaction were studied further in guinea pigs and rats. In the anesthetized rat quinidine significantly increased digoxin, but not digitoxin or ouabain, concentration in plasma during an i.v. infusion of a radiolabeled glycoside. In the anesthetized guinea pig, quinidine markedly increased plasma digoxin, but not digoxigenin or dihydrodigoxin, concentrations as estimated from a competitive binding assay using [3H]ouabain and a partially purified Na+, K+-adenosine triphosphatase preparation. Plasma sodium and potassium concentrations were not altered by quinidine either in control or digoxin-treated guinea pigs. In anesthetized guinea pigs, the quinidine concentrations in plasma was 6.4 +/- 1.1 muM after a 260-min fusion of quinidine at a rate of 26 mumol/kg/hr in control animals and 7.9 +/- 1.6 muM in those which were simultaneously infused with digoxin at a rate of 0.2 mumol/kg/hr. Antiarrhythmic agents, lidocaine, DL-propranolol or verapamil, did not cause a significant change in plasma digoxin concentration in the anesthetized guinea pigs. These results indicate that the binding site involved in quinidine-digoxin interaction has a strict structural requirement with respect ot the glycoside. Additionally, of the four antiarrhythmic drugs, quinidine appears to be the only agent which interacts with digoxin.