Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selective ly attenuates discordantly overexpressed adenosine A, receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [S-35]-label ed EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administer ed to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were kil led at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliqu ots from different tissues and samples were solubilized and assessed for ra dioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was depos ited into the lung. The concentration of the drug in the lung at 0, 6, 24 4 8, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 mug equivalents, respectively. Only a small amount of the radi oactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the adm inistered dose was excreted in the urine, which represented the major pathw ay of elimination. In postlabeling studies, intact full-length EPI-2010 cou ld only be detected in the lung. Autoradiographic analysis after inhalation of [35S]-labeled EPI-2010 showed a relatively uniform deposition of drug t hroughout the lung. The aerosolized EPI-2010 did not have any significant s ystemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovasc ular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic b ioavailability may be contraindicated.