CHARACTERIZATION OF THE TRANSPORT OF A CATIONIC OCTAPEPTIDE, OCTREOTIDE, IN RAT BILE CANALICULAR MEMBRANE - POSSIBLE INVOLVEMENT OF P-GLYCOPROTEIN

The cyclic cationic octapeptide octreotide is known to be taken up by hepatocytes, with more than 70% of an intravenous dose being excreted into bile in unchanged form. We have already reported that a transport er other than the canalicular multispecific organic anion transporter (cMOAT) is responsible for the biliary excretion of octreotide in vivo . The aim of this study is to obtain an insight into the transporter o f octreotide in bile canalicular membrane. The effect of various compo unds on the ATP-dependent uptake of octreotide by rat bile canalicular membrane vesicles (CMV) was investigated. The ATP-dependent uptake of [C-14]octreotide by CMV was inhibited by verapamil, vincristine and P SC833 in a concentration-dependent manner, the maximum inhibitory effe cts of these compounds being almost equal to that of excess unlabeled octreotide, while taurocholic acid (TCA) caused no inhibition at conce ntrations much higher than the K-m of TCA uptake by CMV. Mutual inhibi tion between octreotide and dinitrophenylglutathione (DNP-SG), a repre sentative substrate for cMOAT was only minor and could only be observe d at concentrations much higher than the K-m for each ligand uptake. T o examine the contribution of P-glycoprotein to the biliary excretion of octreotide irt vice, biliary excretion of octreotide was compared b etween P-glycoprotein-induced rats by phenothiazine (PTZ) treatment an d normal rats. A significant increase in the biliary excretion rate wa s observed in PTZ-treated rats. Only a slight decrease in biliary excr etion was observed mdr1a knock-out mice compared with normal mice, whi ch may be explained by the associated induction of mdr1b. These result s demonstrate that the transporter for octreotide is different from cM OAT and the bile acid transporter. The involvement of P-glycoprotein i n the biliary excretion of octreotide is suggested.