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Research ArticleArticle

Differences in the Pharmacokinetics of 4-Amino-3-Chlorophenyl Hydrogen Sulfate, a Metabolite of Resatorvid, in Rats and Dogs

Fumihiro Jinno, Toshiyuki Takeuchi, Yoshihiko Tagawa, Takahiro Kondo, Tomoo Itoh and Satoru Asahi
Drug Metabolism and Disposition April 2012, 40 (4) 648-654; DOI: https://doi.org/10.1124/dmd.111.043729
Fumihiro Jinno
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Toshiyuki Takeuchi
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Yoshihiko Tagawa
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Takahiro Kondo
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Tomoo Itoh
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Satoru Asahi
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Abstract

The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([14C]M-III). The elimination half-life of 14C in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [14C]M-III at 0.5 mg/kg to rats and dogs. The in vitro and in vivo plasma protein binding ratios of M-III were relatively high and were the same in both species. The intrinsic clearance (CLint) of M-III in rats was much higher than the glomerular filtration rate in rats. Furthermore, the concentration of [14C]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [14C]M-III in the kidney was very much lower than that in the plasma. These results indicated that M-III was effectively taken up into the kidney and was excreted into the urine in rats; however, in dogs, ineffective renal uptake of M-III was presumed. When [14C]M-III and probenecid were simultaneously and continually infused intravenously to rats, the CLint of M-III decreased with increasing plasma concentrations of probenecid, indicating that kidney uptake of M-III in rats was inhibited by probenecid. It was also thought that uptake by the organic anion transport system(s) in the basolateral membrane is involved in the renal uptake of M-III in rats. The pharmacokinetic differences of M-III between rats and dogs are considered to be mainly caused by the difference in the urinary excretion via the renal distribution processes.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.043729.

  • ABBREVIATIONS:

    TAK-242
    ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate, resatorvid
    HPLC
    high-performance liquid chromatography
    AUC
    area under the time-concentration curve
    GFR
    glomerular filtration rate
    OAT/Oat
    organic anion transporter
    BLM
    basolateral membrane
    CLrenal
    renal clearance.

  • Received November 23, 2011.
  • Accepted December 27, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

SPECIES DIFFERENCE IN RENAL UPTAKE

Fumihiro Jinno, Toshiyuki Takeuchi, Yoshihiko Tagawa, Takahiro Kondo, Tomoo Itoh and Satoru Asahi
Drug Metabolism and Disposition April 1, 2012, 40 (4) 648-654; DOI: https://doi.org/10.1124/dmd.111.043729

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Research ArticleArticle

SPECIES DIFFERENCE IN RENAL UPTAKE

Fumihiro Jinno, Toshiyuki Takeuchi, Yoshihiko Tagawa, Takahiro Kondo, Tomoo Itoh and Satoru Asahi
Drug Metabolism and Disposition April 1, 2012, 40 (4) 648-654; DOI: https://doi.org/10.1124/dmd.111.043729
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