ABSORPTION, TISSUE DISTRIBUTION AND IN-VIVO STABILITY IN RATS OF A HYBRID ANTISENSE OLIGONUCLEOTIDE FOLLOWING ORAL-ADMINISTRATION

In vivo stability and oral bioavailability of an oligodeoxynucleotide phosphorothioate containing segments of 2'-O-methyloligoribonucleotide phosphorothioates at both the 3'- and 5'-ends (hybrid oligonucleotide ) were studied. A 25-mer S-35-labeled hybrid oligonucleotide was admin istered to rats by gavage at a dose of 50 mg/kg body weight. HPLC anal ysis revealed that this hybrid oligonucleotide was stable in the gastr ointestinal tract for up to 6 hr following oral administration. Radioa ctivity associated with the hybrid oligonucleotide was detectable in p ortal venous plasma, systemic plasma, various tissues, and urine. Inta ct hybrid oligonucleotide was detected, by HPLC analysis, in portal ve nous plasma, systemic plasma, and various tissues. The majority of the radioactivity in urine was associated with degradative products with lower molecular weights, but the intact form was also detected. In sum mary, the hybrid oligonucleotide was absorbed intact through the gastr ointestinal tract, indicating the possibility of oral administration o f oligonucleotides, a finding that may be important in the development of antisense oligonucleotides as therapeutic agents.