Clinically, the administration of quinidine to digitalized patients results in an elevation of serum digoxin concentration. It has been suggested that quinidine displaces tissue-bound digoxin and that renal digoxin clearance is reduced. We studied the influence of digoxin-quinidine interaction on 125I-digoxin uptake by various rat tissues in vitro, employing the tissue slice method. S/M digoxin ratios were kidney 1.72 +/- 0.24 (mean +/- S.D.), heart 2.36 +/- 0.31, muscle 2.05 +/- 0.21 (n = 23 for each), and fat 0.25 +/- 0.10 (n = 9). Addition of quinidine to the incubation medium resulted in a 17.4% reduction of digoxin uptake by kidney tissue to 1.42 +/- 0.38 (n = 24) (p < 0.01). Quinidine failed to reduce digoxin uptake in both heart and striated muscle. Metabolic blockade resulted in a significant reduction in digoxin uptake in kidney slices from 1.93 +/- 0.23 to 1.34 +/- 0.18 with DNP (n = 10) and to 1.30 +/- 0.15 (n = 10) with sodium azide (p < 0.001). Digoxin uptake in either heart or muscle was uninfluenced by metabolic blockers. We conclude that active energy-dependent transport mechanism for digoxin exists in renal cortical tissue. This mechanism is inhibited by either quinidine or metabolic blockers. In contrast, uptake in heart or muscle represents a different transport mechanism unaffected by quinidine or metabolic blockers.