PHARMACOKINETICS OF ANTISENSE OLIGONUCLEOTIDES

Antisense oligonucleotides are promising therapeutic agents for the tr eatment of life-threatening diseases. Intravenous injection of phospho diester 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 phosp horothioate (S-oligonucleotide) in animals by the intravenous route re veals 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 oligonucleot ide was administered subcutaneously. In contrast, methylphosphonate ol igonucleotides 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 oligonuc leotide. The S-oligonucleotide was primarily excreted in urine. Up to 30% was excreted in the first 24 hours. Repeated daily intravenous inj ections of a 25-mer S-oligonucleotide into rats showed that the concen trations in the plasma an at steady-state during the 8 days' administr ation. The data represented here support the potential utility of phos phorothioate and methylphosphonate oligonucleotides as therapeutic age nts in vivo.