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Research ArticleArticle

Development of a Hepatocyte-Specific Prostaglandin E1Polymeric Prodrug and Its Potential for Preventing Carbon Tetrachloride-Induced Fulminant Hepatitis in Mice

Ken Akamatsu, Yasuomi Yamasaki, Makiya Nishikawa, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics September 1999, 290 (3) 1242-1249;
Ken Akamatsu
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Yasuomi Yamasaki
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Makiya Nishikawa
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Yoshinobu Takakura
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Mitsuru Hashida
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Abstract

A polymeric prodrug of prostaglandin E1(PGE1) was synthesized using galactosylated poly(l-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(l-glutamic acid hydrazide) was prepared by reacting poly(γ-benzyl-l-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. 111In-labeled galactosylated poly(l-glutamic acid hydrazide) (111In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas111In-poly(l-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of 111In-Gal-HZ-PLGA. Fractionation of liver cells revealed that 111In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver,111In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE1 or [3H]PGE1was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE1 conjugate. After i.v. injection, [3H]PGE1 conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, 3H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [3H]PGE1. Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE1 conjugate at a dose of 1 mg (0.074 mg PGE1)/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE1 had little effect. These results suggest that the PGE1 conjugate is an excellent polymeric prodrug of PGE1 for hepatitis therapy.

Footnotes

  • Send reprint requests to: Dr. Mitsuru Hashida, Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidasimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail:hashidam{at}pharm.kyoto-u.ac.jp

  • Abbreviations:
    PGE1
    prostaglandin E1
    PLGA
    poly(l-glutamic acid)
    Gal-HZ-PLGA
    galactosylated poly(l-glutamic acid hydrazide)
    PGE1conjugate
    prostaglandin E1 prodrug using Gal-HZ-PLGA as a carrier
    DTPA anhydride
    diethylenetriamine-N,N,N′,N",N"-pentaacetic dianhydride
    GPT
    glutamic pyruvic transaminase
    DP
    degree of polymerization
    IME
    2-imino-2-methoxyethyl-1
    AUC
    area under the plasma concentration-time curve
    CLtotal
    total body clearance
    CLliver
    clearance for liver
    • Received February 8, 1999.
    • Accepted April 27, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 3
1 Sep 1999
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Research ArticleArticle

Development of a Hepatocyte-Specific Prostaglandin E1Polymeric Prodrug and Its Potential for Preventing Carbon Tetrachloride-Induced Fulminant Hepatitis in Mice

Ken Akamatsu, Yasuomi Yamasaki, Makiya Nishikawa, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1242-1249;

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Research ArticleArticle

Development of a Hepatocyte-Specific Prostaglandin E1Polymeric Prodrug and Its Potential for Preventing Carbon Tetrachloride-Induced Fulminant Hepatitis in Mice

Ken Akamatsu, Yasuomi Yamasaki, Makiya Nishikawa, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1242-1249;
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