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Clinical Chemistry 41: 836-843, 1995;
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Clinical Chemistry, Vol 41, 836-843, Copyright © 1995 by American Association for Clinical Chemistry

In vivo stability and disposition of a self-stabilized oligodeoxynucleotide phosphorothioate in rats

R Zhang, Z Lu, X Zhang, H Zhao, RB Diasio, T Liu, Z Jiang and S Agrawal
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.

The use of antisense oligonucleotides represents a novel, genetically based therapy. The biostability and pharmacokinetics of a 33-mer self- stabilized oligodeoxynucleotide with significant anti-HIV activity was determined in rats after intravenous administration of [35S]oligodeoxynucleotide. Plasma disappearance of the labeled oligodeoxynucleotide could be described by a two-compartment model, with half-lives of 0.54 and 41.44 h. The oligodeoxynucleotide in plasma remained mainly intact. Urinary excretion represented the major elimination pathway, with approximately 27% of the administered dose excreted within 24 h and 57% over 240 h. The majority of radioactivity in urine was attached to degradative products. Fecal excretion was a minor elimination pathway. A wide tissue distribution of the oligonucleotide was observed, with the majority of radioactivity in most tissues being intact. Compared with other linear oligonucleotide phosphorothioates, the self-stabilized oligonucleotide was more stable in vivo, which may be important in development of antisense oligonucleotides as therapeutic agents.


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