Oromucosal interferon therapy: pharmacokinetics and pharmacodynamics.
Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN-alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN-responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN-alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells.
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Laboratory of Viral Oncology, UPR 9045 CNRS, Institut de Recherches sur le Cancer/IFR Y1221, Villejuif, France.
Meritet
J F
JF
Maury
C
C
Lasfar
A
A
Weill
D
D
Tovey
M G
MG
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D000284:Administration, Oral; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006403:Hematologic Tests; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007370:Interferon Type I / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009061:Mouth Mucosa; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014018:Tissue Distribution
D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D011994:Recombinant Proteins; D015088:2',5'-Oligoadenylate Synthetase