In vivo stability and kinetics of absorption and disposition of 3' phosphopropyl amine oligonucleotides

• Published in: Nucleic acids research 1992-01, Vol.20 (2), p.307-314
• Main Authors: Zendegui, Joseph G., Vasquez, Karen M., Tinsley, John H., Kessler, Donald J., Hogan, Michael E.
• Format: Article
• Language: English
• Subjects: Absorption; Animals; Antineoplastic agents; Base Sequence; Biological and medical sciences; Female; General aspects; Injections, Intraperitoneal; Kinetics; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Oligodeoxyribonucleotides - pharmacokinetics; Organophosphorus Compounds - pharmacokinetics; Pharmacology. Drug treatments; Propylamines - pharmacokinetics; Tissue Distribution
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/20.2.307

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.