T. Yamada et al., CHARACTERIZATION OF THE TRANSPORT OF A CATIONIC OCTAPEPTIDE, OCTREOTIDE, IN RAT BILE CANALICULAR MEMBRANE - POSSIBLE INVOLVEMENT OF P-GLYCOPROTEIN, Biological & pharmaceutical bulletin, 21(8), 1998, pp. 874-878
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.