Carrier-mediated hepatic uptake of the cationic cyclopeptide, octreotide, in rats. Comparison between in vivo and in vitro.

The plasma concentration and biliary excretion profiles of a cationic cyclic octapeptide, octreotide, were compared between control rats and rats given an intravenous infusion of a bile acid, taurocholate (TCA), and an organic anion, dibromosulfophthalein (DBSP). Both TCA and DBSP reduced the plasma elimination and biliary excretion of octreotide after its intravenous bolus administration. Two mechanisms accounting for this phenomenon were considered a priori: decreased hepatic uptake from blood to liver and decreased biliary excretion from liver to bile. The tissue uptake clearance (CLup) of octreotide in plasma and several tissues was determined, and extensive uptake of octreotide (0.20 ml/min/g liver) was observed only in liver. The kinetic analysis indicated that CLup in liver fell to 10% of controls after administration of both TCA and DBSP. To compare CLup between in vivo and in vitro, the initial velocity of octreotide uptake by isolated hepatocytes and primary cultured hepatocytes was measured. The estimated kinetic parameters KM and Vmax were approximately 100 microM and 200 pmol/min/10(6) cells in both systems, respectively. Hepatic uptake clearance estimated from the in vitro data was comparable with that observed in vivo. Biliary excretion of octreotide is reduced in Eisai hyperbilirubinemic rats (EHBRs), which have a heredity defect of multispecific organic anion transporter on the bile canalicular membrane, compared with that of Sprague-Dawley rats. The kinetic analysis demonstrated that the hepatic uptake was reduced in EHBRs. The uptake study using primary cultured hepatocytes suggested that a high level of unidentified endogenous substrate(s) in EHBR plasma may be responsible for the reduction of hepatic uptake of octreotide in EHBRs. In conclusion, we have demonstrated in vivo that carrier-mediated hepatic uptake of octreotide is inhibited by TCA and DBSP and that the CLup obtained in vivo is comparable with the CLup obtained in vitro in isolated hepatocytes and primary cultured hepatocytes.