Masereeuw R, Moons M M, Russel F G
233 Department of Pharmacology, Faculty of Medical Sciences, University of Nijmegen, Netherlands.
Eur J Pharmacol. 1997 Mar 5;321(3):315-23. doi: 10.1016/s0014-2999(96)00957-0.
Rhodamine 123 has been shown to be a substrate for P-glycoprotein in multidrug resistant cells. In the present investigation the disposition of rhodamine 123 was studied in the isolated perfused rat kidney. After exposing the kidneys to perfusate concentrations ranging from 10 to 1000 ng/ml, the renal clearance was 4-1 times the clearance by glomerular filtration, respectively, indicating active and saturable secretion of rhodamine 123. The rate-limiting step in secretion was found to be membrane passage from cell to tubular lumen. Suprisingly, renal clearance was not influenced by the P-glycoprotein inhibitors cyclosporin A or digoxin. However, pretreatment of the kidneys with verapamil and quinidine (inhibitors of both P-glycoprotein and organic cation transport) or cimetidine (organic cation transport inhibitor) resulted in a significantly reduced rhodamine 123 clearance, indicating that the renal organic cation carrier may be involved in active secretion. Rhodamine 123 accumulated extensively in the isolated perfused rat kidney; tissue concentrations of 270-360 times the perfusate concentration were determined. Similar accumulation ratios at different perfusate concentrations were found, suggesting that the compound enters the tubular cells by (facilitated) diffusion. In conclusion, rhodamine 123 accumulated 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.
罗丹明123已被证明是多药耐药细胞中P-糖蛋白的底物。在本研究中，对罗丹明123在离体灌注大鼠肾脏中的处置情况进行了研究。将肾脏暴露于浓度范围为10至1000 ng/ml的灌注液中后，肾脏清除率分别为肾小球滤过清除率的4至1倍，表明罗丹明123存在主动且可饱和的分泌。发现分泌的限速步骤是从细胞到肾小管腔的膜转运。令人惊讶的是，肾脏清除率不受P-糖蛋白抑制剂环孢素A或地高辛的影响。然而，用维拉帕米和奎尼丁（P-糖蛋白和有机阳离子转运的抑制剂）或西咪替丁（有机阳离子转运抑制剂）对肾脏进行预处理会导致罗丹明123清除率显著降低，表明肾脏有机阳离子载体可能参与主动分泌。罗丹明123在离体灌注大鼠肾脏中大量蓄积；测定的组织浓度为灌注液浓度的270至360倍。在不同灌注液浓度下发现了相似的蓄积率，表明该化合物通过（易化）扩散进入肾小管细胞。总之，罗丹明123在离体灌注大鼠肾脏中大量蓄积，肾脏主动分泌似乎主要由有机阳离子载体介导，而非P-糖蛋白。
