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Faculty of Pharmaceutical Sciences, University of Tokyo (T.Y.,
K.N., T.T., Y.S.) and
Pharmaceutical Division, Sandoz Pharma Ltd.
(M.L).
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 ~100 µM and 200 pmol/min/106 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.
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