IN-VIVO STABILITY AND DISPOSITION OF A SELF-STABILIZED OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE IN RATS

The use of antisense oligonucleotides represents a novel, genetically based therapy. The biostability and pharmacokinetics of a 33-mer self- stabilized oligodeoxynucleotide with significant anti-HIV activity was determined in rats after intravenous administration of [S-35]oligodeo xynucleotide. Plasma disappearance of the labeled oligodeoxynucleotide could be described by a two-compartment model, with half-lives of 0.5 4 and 41.44 h. The oligodeoxynucleotide in plasma remained mainly inta ct. Urinary excretion represented the major elimination pathway, with similar to 27% of the administered dose excreted within 24 h and 57% o ver 240 h. The majority of radioactivity in urine was attached to degr adative products. Fecal excretion was a minor elimination pathway. A w ide tissue distribution of the oligonucleotide was observed, with the majority of radioactivity in most tissues being intact. Compared with other linear oligonucleotide phosphorothioates, the self-stabilized ol igonucleotide was more stable in vivo, which may be important in devel opment of antisense oligonucleotides as therapeutic agents.