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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Copyright © 2001 American Thoracic Society
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