Hepatic Uptake of Octreotide,a Long-Acting Somatostatin Analogue,via a Bile Acid Transport System |
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Authors: | Terasaki Tetsuya Mizuguchi Hiroko Itoho Chizuru Tamai Ikumi Lemaire Michel Tsuji Akira |
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Affiliation: | (1) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, Kanazawa, 920, Japan;(2) Present address: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku 7-3-1, Tokyo, 113, Japan;(3) Biopharmaceutical Department, Sandoz Pharma, 4002 Basle, Switzerland |
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Abstract: | The hepatic transport mechanism of octreotide (Sandostatin®), a somatostatin analogue, was studied using freshly prepared rat hepatocytes. The initial uptake rate of octreotide represented exclusively a saturable transport process. The half-saturation constant, Kt, and the maximum uptake-rate, Jmax, for the uptake of octreotide were 91.1 ± 28.4 µM and 104.6 ± 19.7 pmol/mg protein/min, respectively. An energy requirement was demonstrated for [14C]octreotide uptake since metabolic inhibitors (DNP, rotenone, antimycin and NaCN) significantly reduced the initial uptake rate. [14C]octreotide uptake was also significantly inhibited by ouabain. [14C]octreotide uptake was reduced in the absence of Na+ in the uptake medium. [14C]octreotide uptake was significantly inhibited by bile acids, iodipamide, d-tubocurarine, whereas it was not inhibited by bilirubin, TEMA and insulin. Competitive inhibition of taurocholic acid was observed for octreotide uptake with the inhibition constant, Ki, of 82 ± 17 µM. Moreover, a significant inhibitory effect of octreotide was observed for the Na + dependent uptake of [14C]taurocholic acid. These results suggest that octreotide is transported into hepatocytes via a bile acid carrier-mediated system. |
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Keywords: | octreotide sandostatin® hepatic transport bile acid biliary secretion carrier-mediated transport |
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