TY - JOUR T1 - <em>p</em>-Glycoprotein-Mediated Transport of a Fluorescent Rapamycin Derivative in Renal Proximal Tubule JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 440 LP - 444 VL - 282 IS - 1 AU - David S. Miller AU - Gert Fricker AU - Juergen Drewe Y1 - 1997/07/01 UR - http://jpet.aspetjournals.org/content/282/1/440.abstract N2 - The transport of a fluorescent rapamycin derivative was measured in killifish (Fundulus heteroclitus) renal proximal tubules by means of confocal microscopy and image analysis. Renal cells and tubular lumens rapidly accumulated the rapamycin analog from the medium and attained steady state within 60 min. At steady state, luminal fluorescence intensity was two to four times higher than cellular fluorescence. Cellular fluorescence intensity was a linear function of medium substrate concentration and was not affected by any treatment used. In contrast, luminal fluorescence exhibited a saturable component as the medium concentration of the rapamycin derivative was increased. Secretion into the lumen was blocked by KCN, rapamycin, cyclosporin A and substrates for p-glycoprotein (verapamil, PSC-833 and FK506), but not by substrates for the renal organic anion or organic cation transport systems, such as p-aminohippurate, leukotriene C4 or tetraethylammonium. Finally, rapamycin blockedp-glycoprotein-mediated secretion of a fluorescent cyclosporin A derivative. The data are consistent with the fluorescent rapamycin analog entering proximal tubule cells by simple diffusion and then being pumped into the tubular lumen byp-glycoprotein. They suggest that the parent compound, rapamycin, would be handled similarly. The American Society for Pharmacology and Experimental Therapeutics ER -