In vivo stability, disposition and metabolism of a "hybrid" oligonucleotide phosphorothioate in rats

Ruiwen Zhang, Zhihong LU, Hui Zhao, Xueshu Zhang, Robert B. Diasio, Ivan Habus, Zhiwei Jiang, Radhakrishnan P. Iyer, Dong Yu, Sudhir Agrawal

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Oligodeoxynucleotide phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.

Original languageEnglish (US)
Pages (from-to)545-556
Number of pages12
JournalBiochemical Pharmacology
Volume50
Issue number4
DOIs
StatePublished - Aug 8 1995

Keywords

  • HIV
  • antisense oligodeoxynucleotide phosphorothioate
  • biostability
  • metabolism
  • pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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    Zhang, R., LU, Z., Zhao, H., Zhang, X., Diasio, R. B., Habus, I., Jiang, Z., Iyer, R. P., Yu, D., & Agrawal, S. (1995). In vivo stability, disposition and metabolism of a "hybrid" oligonucleotide phosphorothioate in rats. Biochemical Pharmacology, 50(4), 545-556. https://doi.org/10.1016/0006-2952(95)00159-W