To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cl_dig) and the Cl_dig/Cl_cr ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Cl_cr, which was accompanied by an increase in Cl_dig from 57.5±32, and 60.7±27.3 (duplicate measurements) to 103.9±55.4 (p<0.01) and="" 103.8±46.5="" ml="">^–1 (p<0.01).>_dig/Cl_cr rose from 0.60±0.24 and 0.61±0.16 to 0.91±0.31 and 0.91±0.21, respectively (bothp<0.005). serum="" digoxin="" concentration="" declined="" from="" 1.24±0.35="" and="" 1.19±0.40="" to="" 1.02±0.35="" and="" 0.97±0.32="" µg/l="">p<0.01) during="" the="" high="" sodium="" diet.="" in="" the="" furosemide="" —="" induced="" natriuresis="" (6="" patients),="" changes="" in="" na="" excretion="" and="" v="" were="" a="" multiple="" of="" those="" caused="" by="" na="" loading,="" but="" the="">_dig/Cl_cr ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin.