Recently quinidine and verapamil have been reported to cause toxic accumulation of digoxin due to mainly decrease in the renal secretion of the cardiac glycoside. Because these drugs do not alter GFR, it was assumed that the renal tubular secretion of digoxin is inhibited by them. We studied the characteristics of the renal cortical specific binding for digoxin in the rat kidney, and the antagonistic effects of quinidine and verapamil on digoxin uptake by the kidney slices. Specific binding of digoxin was documented in the renal slices with B max of 42.34 pmol/gr and Kd of 7.6 pmol/gr. The addition of quinidine in therapeutic concentrations (6.7 microM) caused a mean 23% reduction of digoxin uptake by the kidney slice (p less than 0.01). When quinidine concentrations were elevated above the therapeutic range there was additional reduction in digoxin uptake; 84 mM quinidine caused a mean 61% reduction (p less than 0.0001). A similar interaction was documented with verapamil; therapeutic concentrations (550 mM) of the drug caused 15% reduction in digoxin uptake. Further increase in verapamil concentration resulted in additional reduction in digoxin uptake; the maximal concentration used (42 microM) caused 60% decrease in uptake (p less than 0.0001). The inhibition of the renal uptake of digoxin caused by quinidine and verapamil in conjunction with the pharmacokinetic studies, which have shown that both drugs decrease the renal clearance of digoxin without changing GFR, support the suggestion that they inhibit the renal tubular secretion of digoxin.