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Synthesis and Pharmacokinetics of a New Liver-Specific Carrier, Glycosylated Carboxymethyl-Dextran, and Its Application to Drug Targeting

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Abstract

To develop a new carrier system for hepatic targeting, carboxymethyl-dextran (CMD) was modified with galactose and mannose residues (Gal-CMD, Man-CMD), and their disposition characteristics were studied in mice using 14C-labeled dextran. At a dose of 1 mg/kg, i.v.-injected Gal-CMD and Man-CMD rapidly accumulated in the liver parenchymal and nonparenchymal cells, respectively, because of their preferential uptake via carbohydrate receptors in these cells. Pharmacokinetic analysis revealed that their uptake rates were sufficiently large for selective drug targeting. Targeting of cytosine β-D-arabinoside (araC) was studied using Gal-CMD as a specific carrier to the hepatocytes. From the conjugate of araC with Gal-CMD, araC was released with a half-life of 36 hr in phosphate buffer (pH 7.4) and 23 hr in plasma. An in vivo biodistribution study demonstrated a disposition profile of the conjugated araC similar to that of the carrier, and selective delivery to hepatocytes of up to 80% of the dose was achieved. These findings suggest that glycosylated CMDs are carriers with a high affinity to liver parenchymal or nonparenchymal cells without any affinity to other tissues.

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Authors and Affiliations

  1. Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-01, Japan

    Makiya Nishikawa, Akiko Kamijo, Takuya Fujita, Yoshinobu Takakura & Mitsuru Hashida

  2. Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, 573-01, Japan

    Hitoshi Sezaki

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  1. Makiya Nishikawa
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  2. Akiko Kamijo
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  5. Hitoshi Sezaki
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  6. Mitsuru Hashida
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Nishikawa, M., Kamijo, A., Fujita, T. et al. Synthesis and Pharmacokinetics of a New Liver-Specific Carrier, Glycosylated Carboxymethyl-Dextran, and Its Application to Drug Targeting. Pharm Res 10, 1253–1261 (1993). https://doi.org/10.1023/A:1018949109004

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