RHODAMINE-123 ACCUMULATES EXTENSIVELY IN THE ISOLATED-PERFUSED RAT-KIDNEY AND IS SECRETED BY THE ORGANIC CATION SYSTEM

Rhodamine 123 has been shown to be a substrate for P-glycoprotein in m ultidrug resistant cells. In the present investigation the disposition of rhodamine 123 was studied in the isolated perfused rat kidney. Aft er exposing the kidneys to perfusate concentrations ranging from 10 to 1000 ng/ml, the renal clearance was 4-1 times the clearance by glomer ular filtration, respectively, indicating active and saturable secreti on of rhodamine 123. The rate-limiting step in secretion was found to be membrane passage from cell to tubular lumen. Surprisingly, renal cl earance was not influenced by the P-glycoprotein inhibitors cyclospori n A or digoxin. However, pretreatment of the kidneys with verapamil an d quinidine (inhibitors of both P-glycoprotein and organic cation tran sport) or cimetidine (organic cation transport inhibitor) resulted in a significantly reduced rhodamine 123 clearance, indicating that the r enal organic cation carrier may be involved in active secretion. Rhoda mine 123 accumulated extensively in the isolated perfused rat kidney; tissue concentrations of 270-360 times the perfusate concentration wer e determined. Similar accumulation ratios at different perfusate conce ntrations were found, suggesting that the compound enters the tubular cells by (facilitated) diffusion. In conclusion, rhodamine 123 accumul ated extensively in the isolated perfused rat kidney and active renal secretion appears to be preferentially mediated by the organic cation carrier and not by P-glycoprotein.