IN-VITRO PHARMACOKINETICS OF PHOSPHOROTHIOATE ANTISENSE OLIGONUCLEOTIDES

ISIS 2105 (Afovirsen), a 20-mer phosphorothioate oligonucleotide that inhibits the production of a gene product essential to the growth of h uman papillomavirus, is in phase II clinical trials for the treatment of genital warts induced by human papillomavirus-6 and human papilloma virus-11. The uptake, subcellular distribution and metabolism of ISIS 2105 and three other similar length phosphorothioates have been studie d in a variety of cell lines, Our experiments indicated that ISIS 2105 and other phosphorothioates are internalized and distributed in a tim e-, temperature. Cell association was also influenced by the tissue cu lture medium. Several different analytical techniques revealed that ph osphorothioates were more rapidly degraded in vitro than previously re ported. These data suggest that phosphorothioate oligonucleotide uptak e and stability observed in tissue culture can vary as a function of c ellular assay conditions and analytical methods used. Comparison of th ese results with those obtained in vivo suggests that the pharmacokine tic behavior of this class of compounds cannot necessarily be predicte d from in vitro studies.