Yamada T, Niinuma K, Lemaire M, Terasaki T, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Pharmacol Exp Ther. 1996 Dec;279(3):1357-64.
The hepatobiliary transport and tissue distribution of the cationic cyclooctapeptide octreotide were studies at steady state after its infusion, at various rates, in rats. After an increase in steady-state plasma concentration, marked decrease in the tissue to plasma concentration ratio was observed only in pancreas, the target organ of octreotide. A marked decrease in the biliary excretion clearance, defined with respect to the concentration in the liver, was also observed, suggesting that a transport carrier was involved in the biliary excretion. The plasma elimination and biliary excretion profiles of octreotide were determined in Eisai hyperbilirubinemic rats (EHBR), which have an hereditary defect of the active transport carrier for organic anions in bile canalicular membranes. Although biliary excretion of octreotide was significantly reduced in EHBR, compared with normal Sprague-Dawley rats, no difference was observed in biliary excretion clearance, defined with respect to the concentration in the liver, between Sprague-Dawley rats and EHBR. On the other hand, the liver to plasma concentration ratio in EHBR fell to half that in Sprague-Dawley rats. These results suggest that the decreased biliary excretion of octreotide in EHBR is due not to reduced biliary excretion ability but to reduced hepatic uptake of octreotide. We studied in vitro transport using bile canalicular membrane vesicles. A significant increase in the transport of octreotide by bile canalicular membrane vesicles was observed in the presence of ATP, and the estimated kinetic parameters K(m) and Vmax were 6.5 microM and 370 pmol/min/mg of protein, respectively. Similar ATP-dependent uptake was observed in bile canalicular membrane vesicles prepared from EHBR. We concluded that the biliary excretion of octreotide is by ATP-dependent primary active transport and that the carrier system for octreotide differs from the so-called "canalicular multispecific organic anion transporter," which is absent in EHBR.
在大鼠中，以不同速率输注阳离子环八肽奥曲肽后，对其肝胆转运和组织分布进行了稳态研究。稳态血浆浓度升高后，仅在奥曲肽的靶器官胰腺中观察到组织与血浆浓度比显著降低。还观察到相对于肝脏中的浓度定义的胆汁排泄清除率显著降低，这表明胆汁排泄涉及一种转运载体。在艾塞那（Eisai）高胆红素血症大鼠（EHBR）中测定了奥曲肽的血浆消除和胆汁排泄情况，该大鼠在胆小管膜中存在有机阴离子主动转运载体的遗传性缺陷。尽管与正常的斯普拉格 - 道利大鼠相比，奥曲肽在EHBR中的胆汁排泄显著减少，但在斯普拉格 - 道利大鼠和EHBR之间，相对于肝脏中的浓度定义的胆汁排泄清除率没有差异。另一方面，EHBR中的肝脏与血浆浓度比降至斯普拉格 - 道利大鼠的一半。这些结果表明，EHBR中奥曲肽胆汁排泄减少不是由于胆汁排泄能力降低，而是由于奥曲肽肝脏摄取减少。我们使用胆小管膜囊泡进行了体外转运研究。在ATP存在下，观察到胆小管膜囊泡对奥曲肽的转运显著增加，估计的动力学参数K(m)和Vmax分别为6.5 microM和370 pmol/min/mg蛋白质。在从EHBR制备的胆小管膜囊泡中也观察到类似的ATP依赖性摄取。我们得出结论，奥曲肽的胆汁排泄是通过ATP依赖性原发性主动转运，并且奥曲肽的载体系统不同于所谓的“胆小管多特异性有机阴离子转运体”，后者在EHBR中不存在。
