title: In vivo stability and disposition of a self-stabilized oligodeoxynucleotide phosphorothioate in rats.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: R B
authors.initials: RB
authors.lastname: Diasio
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: Z
authors.initials: Z
authors.lastname: Jiang
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
mesh_terms: 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
chemical_list: D016376:Oligonucleotides, Antisense; D013873:Thionucleotides