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Research ArticleArticle

Renal Drug Targeting Using a Vector “Alkylglycoside”

Kokichi Suzuki, Hiroshi Susaki, Satoshi Okuno and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 57-64;
Kokichi Suzuki
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Hiroshi Susaki
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Satoshi Okuno
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Yuichi Sugiyama
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Abstract

A specific sugar-modified peptide has previously been shown to have renal targeting potential in vivo and to have a specific binding site which has been identified in the kidney membrane fraction. In this report, we studied the inhibitory effects of glycosylated derivatives on the binding of [3H]Glc-O-C8-AVP [a glucosylated derivative of Arg8-vasopressin (AVP),Kd = 55 nM] to clarify the structural requirements necessary for renal recognition. Glc-S-C7-Me (octyl β-d-thioglucoside) markedly inhibited the binding, to a much greater extent than Glc-O-C7-Me (octyl β-d-glucoside) and Gal-S-C7-Me (octyl β-d-thiogalactoside). Also, [3H]Glc-S-C7-Me was shown to have a specific binding site on the kidney membrane (Kd = 17 nM, Bmax = 24 pmol/mg protein) rather than the liver membrane and, in addition, Glc-S-C7-Me exhibited effective and selective renal uptake in vivo. To examine the possibility that Glc-S-C7-Me might be of practical use as a renal targeting vector, AVP, tryptamine and 4-nitrobenz-2-oxa-1,3-diazole were modified with Glc-S-C8- and the tissue uptake of the resulting derivatives was evaluated. All of these derivatives showed clear renal targeting potential because the apparent uptake clearance by the kidney was greater than 3 ml/min/g kidney in each case. As far as the AVP derivatives were concerned, derivatives having different numbers of methylene groups were compared with Glc-S-C8-AVP. Glc-S-C11-AVP exhibited increased kidney targeting potential, whereas that of Glc-S-C5-AVP was reduced. These differences suggest that the “alkylglycoside” moiety is important for renal uptake. In addition, these renally targeted derivatives inhibited the binding of [3H]Glc-S-C7-Me to the kidney membrane fraction. Our findings allow us to conclude that the alkylglycoside is a suitable candidate vector for renal targeting.

Footnotes

  • Send reprint requests to: Kokichi Suzuki, Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.

  • ↵1 Present address: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.

  • ↵2 Present address: New Product Research Laboratories IV, Daiichi Pharmaceutical Co., Ltd., 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan.

  • ↵3 Present address: Medicinal Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-50 Kawagishi 2-chome, Toda-shi, Saitama 335-8505, Japan.

  • Abbreviations:
    AVP
    arginine vasopressin
    Bmax
    maximum binding capacity
    CLup
    uptake clearance
    CLup
    app, apparent uptake clearance
    DCC
    dicyclohexylcarbodiimide
    DMF
    N,N-dimethylformamide
    Gal-S-C7-Me
    octyl β-d-thiogalactoside
    Glc-O-C5-Me
    hexyl β-d-glucoside
    Glc-O-C7-Me
    octyl β-d-glucoside
    Glc-S-C7-Me
    octyl β-d-thioglucoside
    HOCO-C5-NBD
    N-[7-nitrobenz-2-oxa-1,3-diazole-4-yl]aminohexanoic acid
    HOSu
    N-hydroxysuccinimide
    NBD
    4-nitrobenz-2-oxa-1,3-diazole
    TFA
    trifluoroacetic acid
    HPLC
    high-performance liquid chromatography
    BSA
    bovine serum albumin
    AUC
    area under the curve
    IC50
    50% inhibitory concentration
    CHAPS
    3-[cholamidopropyl)dimethylamino]-1-propanesulfonate
    • Received April 28, 1998.
    • Accepted July 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Renal Drug Targeting Using a Vector “Alkylglycoside”

Kokichi Suzuki, Hiroshi Susaki, Satoshi Okuno and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 57-64;

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Research ArticleArticle

Renal Drug Targeting Using a Vector “Alkylglycoside”

Kokichi Suzuki, Hiroshi Susaki, Satoshi Okuno and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 57-64;
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