Summary
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.
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Agrawal, S., Temsamani, J., Galbraith, W. et al. Pharmacokinetics of Antisense Oligonucleotides. Clin. Pharmacokinet. 28, 7–16 (1995). https://doi.org/10.2165/00003088-199528010-00002
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DOI: https://doi.org/10.2165/00003088-199528010-00002