title: Pharmacokinetics of antisense oligonucleotides.
abstract: Antisense oligonucleotides are promising therapeutic agents for the treatment of life-threatening diseases. Intravenous injection of phosphodiester oligonucleotide analogue (P-oligonucleotide) in monkeys shows that the oligonucleotide is degraded rapidly in the plasma with a half-life of about 5 minutes. Administration of a single dose of the phosphorothioate (S-oligonucleotide) in animals by the intravenous route reveals biphasic plasma elimination. An initial short half-life (0.53 to 0.83 hours) represents distribution out of the plasma compartment and a second long half-life (35 to 50 hours) represents elimination from the body. This elimination half-life was similar when the oligonucleotide was administered subcutaneously. In contrast, methylphosphonate oligonucleotides have an elimination half-life of 17 minutes in mice. S-Oligonucleotide was distributed into most of organs of rats and mice. Liver and kidney were the 2 organs with highest uptake of the oligonucleotide. The S-oligonucleotide was primarily excreted in urine. Up to 30% was excreted in the first 24 hours. Repeated daily intravenous injections of a 25-mer S-oligonucleotide into rats showed that the concentrations in the plasma are at steady-state during the 8 days' administration. The data represented here support the potential utility of phosphorothioate and methylphosphonate oligonucleotides as therapeutic agents in vivo.
authors.affiliation: Hybridon Inc., Worcester, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
authors.forename: J
authors.initials: J
authors.lastname: Temsamani
authors.forename: W
authors.initials: W
authors.lastname: Galbraith
authors.forename: J
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001483:Base Sequence; D002986:Clinical Trials as Topic; D004952:Esters; D006801:Humans; D008969:Molecular Sequence Data; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D016376:Oligonucleotides, Antisense / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds; D013873:Thionucleotides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000998:Antiviral Agents; D004952:Esters; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; D013873:Thionucleotides; C032627:methylphosphonic acid; C079996:GEM91