The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady‐state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within‐subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady‐state biliary clearance of digoxin from control value 134 ± 57 ml/min (mean ± SD) to 87 ± 39 ml/min during treatment with quinine (p<0.05) and from 95 ± 24 to 55 ± 27 ml/min during treatment with quinidine (p<0.01;n= 4). Quinidine reduced the renal clearance of digoxin (155 ± 26 versus 110 ± 21 ml/min) (p<0.05;n= 4), whereas quinine had no such effect (177 ± 40 versus 185 ± 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.Clinical Pharmacology and Therapeutics(1990)47,20–26; doi:10