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Research ArticleArticle

CARRIER-MEDIATED HEPATIC UPTAKE OF THE CATIONIC CYCLOPEPTIDE, OCTREOTIDE, IN RATS

Comparison between In Vivo and In Vitro

Tadashi Yamada, Kayoko Niinuma, Michel Lemaire, Tetsuya Terasaki and Yuichi Sugiyama
Drug Metabolism and Disposition May 1997, 25 (5) 536-543;
Tadashi Yamada
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Kayoko Niinuma
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Michel Lemaire
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Tetsuya Terasaki
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Yuichi Sugiyama
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Comparison between In Vivo and In Vitro

Abstract

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 compareCLup 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 andVmax 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 CLupobtained in vivo is comparable with theCLup obtained in vitro in isolated hepatocytes and primary cultured hepatocytes.

Footnotes

  • Send reprint requests to: Dr. Yuichi Sugiyama, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-Ku, Tokyo 113, Japan.

  • Abbreviations used are::
    DBSP
    dibromosulfophthalein
    PAH
    p-aminohippurate
    TCA
    taurocholic acid
    EHBR
    Eisai hyperbilirubinemic rat
    cMOAT
    canalicular multispecific organic anion transporter
    SDR
    Sprague-Dawley rat
    Cp(t)
    plasma concentration of octreotide
    AUC
    area under the plasma concentration-time curve
    CLtot
    total body clearance
    CLbile,p
    biliary excretion clearance defined with respect to the concentration in plasma
    Xbile
    amount of octreotide excreted into bile
    X(t)
    amount of octreotide in the tissue at time t
    CLup
    the tissue uptake clearance
    GFR
    glomerular filtration rate
    BSA
    bovine serum albumin
    Vmax
    maximal uptake rate
    KM
    Michaelis constant
    Pdiff
    nonspecific uptake clearance
    Qhp
    hepatic plasma flow
    fp
    plasma unbound fraction
    Tmax
    transport maximum
    Kp
    the tissue-to-plasma concentration ratio
    • Received June 3, 1996.
    • Accepted January 28, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 5
1 May 1997
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Research ArticleArticle

CARRIER-MEDIATED HEPATIC UPTAKE OF THE CATIONIC CYCLOPEPTIDE, OCTREOTIDE, IN RATS

Tadashi Yamada, Kayoko Niinuma, Michel Lemaire, Tetsuya Terasaki and Yuichi Sugiyama
Drug Metabolism and Disposition May 1, 1997, 25 (5) 536-543;

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Research ArticleArticle

CARRIER-MEDIATED HEPATIC UPTAKE OF THE CATIONIC CYCLOPEPTIDE, OCTREOTIDE, IN RATS

Tadashi Yamada, Kayoko Niinuma, Michel Lemaire, Tetsuya Terasaki and Yuichi Sugiyama
Drug Metabolism and Disposition May 1, 1997, 25 (5) 536-543;
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