Am. J. Respir. Crit. Care Med., Volume 163, Number 4, March 2001, 989-993

Absorption, Distribution, Metabolism, and Excretion of a Respirable Antisense Oligonucleotide for Asthma

SHAHID ALI, SHERRY A. LEONARD, CINDY A. KUKOLY, W. JAMES METZGER, WALLACE R. WOOLES, JACQUELINE F. MCGINTY, MAKOTO TANAKA, ANTHONY SANDRASAGRA, and JONATHAN W. NYCE

Department of Molecular Pharmacology and Therapeutics, EpiGenesis Pharmaceuticals Inc., Princeton, New Jersey; Asthma and Allergy Center of Eastern North Carolina, School of Medicine, Greenville, North Carolina; National Jewish Medical And Research Center, Denver, Colorado; Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina; Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina; and Scientific Evaluation Group, Taisho Pharmaceutical Co., Ltd, Toshimaku, Tokyo, Japan

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A₁ receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [³⁵S]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24, 48, 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 µg equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [³⁵S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.

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