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Research ArticleArticle

Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide ,

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kenji Nishimura, Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 37-42;
Hitoshi Ishizuka
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Kumiko Konno
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Hideo Naganuma
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Kenji Nishimura
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Hirokazu Kouzuki
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Hiroshi Suzuki
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Bruno Stieger
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Peter J. Meier
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Yuichi Sugiyama
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Abstract

The mechanism for hepatic uptake of temocaprilat, an angiotensin-converting enzyme inhibitor that is predominantly excreted into bile was studied using isolated rat hepatocytes and COS-7 cells expressing the organic anion transporting polypeptide (oatp1). The uptake of temocaprilat into isolated rat hepatocytes exhibited saturation with a Km of 20.9 μM and a Vmax of 0.21 nmol/min/mg protein. This uptake was temperature sensitive and was significantly reduced by metabolic inhibitors, a sulfhydryl-modifying reagent and an anion-exchange inhibitor, although the replacement of Na+ with Li+ in the medium did not affect the uptake. [3H]Temocaprilat uptake was inhibited by estradiol-17β-d-glucuronide and dibromosulphophthalein, typical substrates for the Na+-independent organic anion transporter, in a concentration-dependent manner, whereas excess estradiol-17β-d-glucuronide did not completely inhibit the uptake. Temocaprilat uptake into COS-7 cells transfected with oatp1 cDNA revealed a concentration-dependency with aKm of 46.7 μM, a value comparable with that obtained in isolated hepatocytes. The contribution of oatp1 to carrier-mediated hepatic uptake of temocaprilat was less than 50% by correcting the uptake clearance with that of estradiol-17β-d-glucuronide. A good linear correlation was observed for the inhibitory effect of angiotensin-converting enzyme inhibitors (benazeprilat, cilazaprilat, delaprilat and enalaprilat) between isolated hepatocytes and oatp1-expressing cells. These data suggest that oatp1, along with another transporter(s), mediates the uptake of angiotensin-converting enzyme inhibitors into rat hepatocytes.

Footnotes

  • Send reprint requests to: Dr. Hitoshi Ishizuka, Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140, Japan.

  • ↵1 This work was supported in part by the Swiss National Science Foundation Grant 31-45536.95 to P.J.M.

  • ↵2 This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, and the Core Research for Evolutional Sciences and Technology of Japan Sciences and Technology Corporation.

  • Abbreviations:
    ACE
    angiotensin-converting enzyme
    oatp1
    organic anion transporting polypeptide
    Ntcp
    Na+/taurocholate co-transporting polypeptide
    cMOAT
    canalicular multispecific organic anion transporter
    E217βG
    estradiol-17β-d-glucuronide
    BSP
    bromosulfophthalein
    DBSP
    dibromosulfophthalein
    DIDS
    4,4′-diisothiocyanostilbene-2,2′-disulfonic acid
    FCCP
    carbonyl cyanide p-(trifluoro-methoxy)phenylhydrazone
    PCMBS
    p-choloromercuriphenylsulfonic acid
    HEPES
    2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid
    SD rats
    Sprague-Dawley rats
    EHBR
    Eisai hyperbilirubinemic rats
    DMEM
    Dulbecco’s modified Eagle’s medium
    • Received January 17, 1998.
    • Accepted May 18, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Research ArticleArticle

Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide ,

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kenji Nishimura, Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 37-42;

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Research ArticleArticle

Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide ,

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kenji Nishimura, Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 37-42;
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