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Vol. 296, Issue 3, 890-897, March 2001
Isis Pharmaceuticals, Inc., Carlsbad, California
Plasma pharmacokinetics, biodistribution, excretion, and metabolism of
four modified 20-mer antisense oligonucleotides targeted to human
intercellular adhesion molecule-1 mRNA have been characterized in rats and compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The modified oligonucleotides contained 2'-O-(2-methoxyethyl)
(2'-O-MOE) ribose sugar modifications on all or a
portion of the nucleotides in the antisense sequence. The
2'-O-MOE-modified oligonucleotides were resistant to
nuclease metabolism in both plasma and tissue. In general, plasma
pharmacokinetics was not substantially altered by addition of the
2'-O-MOE modification to PS ODN. Thus, plasma clearance
was dominated by distribution to tissues, broadly, with less than 10%
of the administered dose excreted in urine or feces over 24 h.
However, the 2'-O-MOE modification combined with the
phosphodiester (PO) backbone exhibited 10-fold more rapid plasma
clearance, with approximately 50% of the dose excreted in urine as
intact oligonucleotide. Consistent with its rapid and extensive
excretion, the PO 2'-O-MOE modification distributed to
very few organs in any substantial amount with the exception of the
kidney. Oligonucleotides that contained phosphorothioate backbones were
highly bound to plasma proteins. Indeed, the primary characteristic
that resulted in the most marked alterations in pharmacokinetics
appeared to be the affinity and capacity of these compounds to bind
plasma proteins. A balance of greater stability supplied by the
2'-O-MOE modification together with maintenance of
plasma protein binding appears to be necessary to ensure favorable pharmacokinetics of this new generation of antisense oligonucleotides.
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