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Research ArticleArticle

Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent

Mitsuo Murata, Ikumi Tamai, Yoshimichi Sai, Osamu Nagata, Hideo Kato, Yuichi Sugiyama and Akira Tsuji
Drug Metabolism and Disposition November 1998, 26 (11) 1113-1119;
Mitsuo Murata
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Ikumi Tamai
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Yoshimichi Sai
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Osamu Nagata
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Hideo Kato
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Yuichi Sugiyama
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Akira Tsuji
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Abstract

HSR-903 is a newly synthesized quinolone antibacterial agent with low toxicity. The biliary and urinary excretion of unchanged HSR-903, its R-isomer, and their glucuronides was determined after iv bolus administration (5 mg/kg) to normal Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic mutant rats (EHBR). The values for the biliary excretion clearance of HSR-903 and its glucuronide in EHBR were decreased to approximately 40 and 2% of those in SDR, respectively, whereas the values for the urinary excretion clearance of HSR-903 and its glucuronide were comparable in SDR and EHBR. The biliary excretion clearance values for the R-isomer and its glucuronide were approximately 3 times greater than those for HSR-903. These results demonstrated that the enantiomers of HSR-903 and their conjugates were excreted into bile in a stereospecific manner. The hepatic uptake of [14C]HSR-903 in vivo was evaluated by means of integration plot analysis. The results indicated that the hepatic uptake of [14C]HSR-903 was very fast and was blood flow-limited. To clarify the mechanism of excretion of HSR-903 into bile, the uptake and efflux of [14C]HSR-903 were studied using isolated hepatocytes from SDR and EHBR. The initial uptake of HSR-903 by hepatocytes was temperature-dependent, saturable, and stereospecific. Unlabeled HSR-903 (S-isomer), the R-isomer, grepafloxacin, and sparfloxacin significantly inhibited the uptake of [14C]HSR-903. The efflux of [14C]HSR-903 from hepatocytes from EHBR was significantly slower than that from hepatocytes from SDR. The addition of sodium azide or bromosulfophthalein reduced the efflux of [14C]HSR-903. These results demonstrate that HSR-903 is actively excreted into bile via the canalicular multispecific organic anion transporter, which is deficient in EHBR.

Footnotes

  • Send reprint requests to: Akira Tsuji, Ph.D., Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan.

  • This research was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan.

  • Abbreviations used are::
    EHBR
    Eisai hyperbilirubinemic mutant rat(s)
    SDR
    Sprague-Dawley rat(s)
    BSP
    bromosulfophthalein
    CLbile
    biliary excretion clearance
    CLurine
    urinary excretion clearance
    cMOAT
    canalicular multispecific organic anion transporter
    Cp,t
    plasma concentration at time t
    Cliver
    t, drug amount per gram of wet tissue at time t
    CLuptake
    hepatic uptake clearance
    Kt
    apparent Michaelis constant
    Jmax
    maximal uptake rate
    kd
    nonsaturable uptake clearance
    PSu,influx
    membrane permeability clearance
    CLint,liver
    intrinsic hepatic uptake clearance
    CLtot
    total body clearance
    • Received December 1, 1997.
    • Accepted May 8, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 11
1 Nov 1998
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Research ArticleArticle

Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent

Mitsuo Murata, Ikumi Tamai, Yoshimichi Sai, Osamu Nagata, Hideo Kato, Yuichi Sugiyama and Akira Tsuji
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1113-1119;

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Research ArticleArticle

Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent

Mitsuo Murata, Ikumi Tamai, Yoshimichi Sai, Osamu Nagata, Hideo Kato, Yuichi Sugiyama and Akira Tsuji
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1113-1119;
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