The effect of digoxin dosage on the digoxin—quinidine interaction in the bile duct-cannulated rat

Abstract

Abstract Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg−1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 μg kg−1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50–80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 μg kg−1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 μg kg−1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the mono-digitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin—quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.