In vivo stability and disposition of a self-stabilized oligodeoxynucleotide phosphorothioate in rats.
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.
Zhang
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Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Lu
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Z
Zhang
X
X
Zhao
H
H
Diasio
R B
RB
Liu
T
T
Jiang
Z
Z
Agrawal
S
S
D000818:Animals; D001483:Base Sequence; D004355:Drug Stability; D005243:Feces / Q000737:chemistry; D006678:HIV / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides