P-glycoprotein- and mrp2-mediated octreotide transport in renal proximal tubule

1 Transepithelial transport of a fluorescent derivative of octreotide (NBD- octreotide) was studied in freshly isolated, functionally intact renal prox imal tubules from killifish (Fundulus heteroclitus). 2 Drug accumulation in the tubular lumen was visualized by means of confoca l microscopy and was measured by image analysis. Secretion of NBD-octreotid e into the tubular lumen was demonstrated and exhibited the all characteris tics of specific and energy-dependent transport. Steady slate luminal fluor escence averaged about five times cellular fluorescence and was reduced to cellular levels when metabolism was inhibited by NaCN. 3 NBD-octreotide secretion was inhibited in a concentration-dependent manne r by unlabelled octreotide, verapamil and leukotriene C-4 (LTC4). Conversel y, unlabelled octreotide reduced in a concentration dependent manner the p- glycoprotein (Pgp)-mediated secretion of a fluorescent cyclosporin A deriva tive (NBDL-CS) and the mrp2-mediated secretion of fluorescein methotrexate (FL-MTX). 4 This inhibition was not due to impaired metabolism or toxicity since octr eotide had no influence on the active transport of fluorescein (FL), a subs trate for the classical renal system. 5 The data are consistent with octreotide being transported across the brus h border membrane of organic anion transport proximal kidney tubules by bot h Pgp and mrp2.