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.