Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration

Sudhir Agrawal, Xueshu Zhang, Zhihong Lu, Hui Zhao, Jeffrey M. Tamburin, Jieming Van, Hongying Cai, Robert B. Diasio, Ivan Habus, Zhiwei Jiang, Radhakrishnan P. Iyer, Dong Yu, Ruiwen Zhang

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

In vivo stability and oral bioavailability of an oligodeoxynucleotide phosphorothioate containing segments of 2′-O-methyloligoribonucleotide phosphorothioates at both the 3′- and 5′-ends (hybrid oligonucleotide) were studied. A 25-mer 35S-labeled hybrid oligonucleotide was administered to rats by gavage at a dose of 50 mg/kg body weight. HPLC analysis revealed that this hybrid oligonucleotide was stable in the gastrointestinal tract for up to 6 hr following oral administration. Radioactivity associated with the hybrid oligonucleotide was detectable in portal venous plasma, systemic plasma, various tissues, and urine. Intact hybrid oligonucleotide was detected, by HPLC analysis, in portal venous plasma, systemic plasma, and various tissues. The majority of the radioactivity in urine was associated with degradative products with lower molecular weights, but the intact form was also detected. In summary, the hybrid oligonucleotide was absorbed intact through the gastrointestinal tract, indicating the possibility of oral administration of oligonucleotides, a finding that may be important in the development of antisense oligonucleotides as therapeutic agents.

Original languageEnglish (US)
Pages (from-to)571-576
Number of pages6
JournalBiochemical Pharmacology
Volume50
Issue number4
DOIs
StatePublished - Aug 8 1995

Keywords

  • HIV
  • antisense oligonucleotides
  • oral bioavailability

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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    Agrawal, S., Zhang, X., Lu, Z., Zhao, H., Tamburin, J. M., Van, J., Cai, H., Diasio, R. B., Habus, I., Jiang, Z., Iyer, R. P., Yu, D., & Zhang, R. (1995). Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration. Biochemical Pharmacology, 50(4), 571-576. https://doi.org/10.1016/0006-2952(95)00160-2