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Research ArticleArticle

Hepatic Disposition and Toxicity of Cationized Goat Immunoglobulin G and Fab Fragments in Isolated Perfused Rat Liver

G. Hong, M. Bazin-Redureau, P. Gires and J. M. Scherrmann
Drug Metabolism and Disposition July 1998, 26 (7) 661-669;
G. Hong
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M. Bazin-Redureau
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P. Gires
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J. M. Scherrmann
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Abstract

Colchicine-specific goat IgG and Fab fragments were cationized by covalent coupling of hexamethylenediamine. The immunoreactivity of antibodies was not changed following cationization. The interaction of125I-radiolabeled native (nIgG and nFab) and cationized immunoglobulin G (cIgG) and Fab fragments (cFab) with liver was investigated using isolated perfused rat liver (IPRL) and isolated rat hepatic parenchymal cells (PCs) and nonparenchymal cells (NPCs) in suspension. 125I-cIgG or125I-cFab were more rapidly cleared from the perfusate than the corresponding native proteins. Both cIgG and cFab declined biexponentially over time in the perfusate. In contrast, the native IgG and Fab decreased monoexponentially. The half-lives of the initial and terminal phases were 5.2 ± 1.6 min and 355.1 ± 17.2 min for cIgG and 14.7 ± 3.4 min and 552.4 ± 23.7 min for cFab. The terminal half-lives of nIgG (467.4 ± 11.6 min) and nFab (880.1 ± 39.6 min) were longer than those of cationized molecules. The biliary protein extraction ratio of cationized IgG and Fab was greater than that of native IgG and Fab: 0.13% (cIgG), 0.02% (nIgG), 0.23% (cFab), and 0.17% (nFab). The uptake of cIgG and cFab by both PCs and NPCs was dose-dependent and was about 6-fold and 8-fold higher than that of their native counterparts, respectively. Throughout the experiment, liver viability was determined, and no toxicity was observed according to physiological analysis (bile flow rate, portal vein pressure, and pH) and biochemical analysis (glucose and hepatic enzymes: alanine transaminase, aspartate transaminase, lactate dehydrogenase) in perfusate.

Footnotes

  • Send reprint requests to: G. Hong, M. D., INSERM U26, Hôpital Fernand Widal, 200, rue du Faubourg Saint-Denis, 75475 Paris, CEDEX 10, France.

  • This work was supported by a grant from INSERM/Ministère de la Défense.

  • Abbreviations used are::
    ALT
    alanine transaminase
    AST
    aspartate transaminase
    AUC
    area under the curve
    BSA
    bovine serum albumin
    cFab
    cationized antigen binding fragments
    cIgG
    cationized immunoglobulin G
    IPRL
    isolated perfused rat liver
    LDH
    lactate dehydrogenase
    nFab
    native antigen binding fragments
    nIgG
    native immunoglobulin G
    NPC
    nonparenchymal cell
    PAGE
    polyacrylamide gel electrophoresis
    PC
    parenchymal cell
    RBC
    red blood cells
    TCA
    trichloroacetic acid
    • Received November 4, 1997.
    • Accepted March 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 7
1 Jul 1998
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Research ArticleArticle

Hepatic Disposition and Toxicity of Cationized Goat Immunoglobulin G and Fab Fragments in Isolated Perfused Rat Liver

G. Hong, M. Bazin-Redureau, P. Gires and J. M. Scherrmann
Drug Metabolism and Disposition July 1, 1998, 26 (7) 661-669;

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Research ArticleArticle

Hepatic Disposition and Toxicity of Cationized Goat Immunoglobulin G and Fab Fragments in Isolated Perfused Rat Liver

G. Hong, M. Bazin-Redureau, P. Gires and J. M. Scherrmann
Drug Metabolism and Disposition July 1, 1998, 26 (7) 661-669;
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