title: In vivo stability and kinetics of absorption and disposition of 3' phosphopropyl amine oligonucleotides.
abstract: Development of oligonucleotide derivatives as therapeutic agents requires an understanding of their pharmacokinetic behavior. The in vivo disposition and stability of a prototype of such compounds are reported here. The compound studied, a relatively G-rich 38 base 3' phosphopropyl amine oligonucleotide (TFO-1), was cleared from the circulation with a half-life of approximately 10 minutes, displaying distribution kinetics consistent with a two compartment model. TFO-1 was also readily absorbed into circulation from the peritoneal cavity. All tissues examined except brain accumulated the compound reaching concentrations calculated to be in the micromolar range. TFO-1 was found to be stable in circulation and in tissues in that a large fraction of intact material was detected 8 hours after injection, as assessed by gel electrophoresis. Approximately 20-30% of the injected dose was excreted in the urine over an 8 hour period. These results suggest that G-rich oligonucleotides, minimally modified at the 3' end, are relatively stable in vivo and have distribution kinetics favorable to use as therapeutic agents.
authors.affiliation: Triplex Pharmaceutical Corporation, The Woodlands, TX 77380.
authors.forename: J G
authors.initials: JG
authors.lastname: Zendegui
authors.forename: K M
authors.initials: KM
authors.lastname: Vasquez
authors.forename: J H
authors.initials: JH
authors.lastname: Tinsley
authors.forename: D J
authors.initials: DJ
authors.lastname: Kessler
authors.forename: M E
authors.initials: ME
authors.lastname: Hogan
mesh_terms: D000042:Absorption; D000818:Animals; D001483:Base Sequence; D005260:Female; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D011437:Propylamines / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D011437:Propylamines