R. Masereeuw et al., RHODAMINE-123 ACCUMULATES EXTENSIVELY IN THE ISOLATED-PERFUSED RAT-KIDNEY AND IS SECRETED BY THE ORGANIC CATION SYSTEM, European journal of pharmacology, 321(3), 1997, pp. 315-323
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.