Absolute Bioavailability of 2â²-O-(2-Methoxyethyl)-Modified Antisense Oligonucleotides following Intraduodenal Instillation in Rats
Three modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA were characterized for their presystemic stability and oral bioavailability compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The three modified oligonu...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 296; no. 3; p. 898 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.03.2001
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Abstract | Three modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA were characterized
for their presystemic stability and oral bioavailability compared with a first-generation phosphorothioate oligodeoxynucleotide
(PS ODN), ISIS 2302. The three modified oligonucleotides contained 2â²- O -(2-methoxyethyl) (2â²- O -MOE) ribose sugar modifications on a portion, or on all of the nucleotides in the antisense sequence. In vitro metabolism
studies conducted in various gastrointestinal and digestive tissue preparations indicated substantial improvement in stability
of 2â²- O -MOE-modified oligonucleotides. In addition, in vivo presystemic stability of these oligonucleotides was monitored in rats
following intraduodenal administration. By 8 h after administration, only chain-shortened metabolites of the PS ODN were recovered
in the gastrointestinal contents. In contrast, approximately 50% of the 2â²- O -MOE ribose-modified (partial) compound remained intact (20-mer) by 8 h following administration. Both of the fully modified
compounds (2â²- O -MOE PO and PS) were completely stable with no measurable metabolites observed within 8 h of administration. The rank order
of bioavailability was ISIS 11159 (full PS, full MOE) < ISIS 2302 (PS ODN) < ISIS 16952 (full PO, full MOE) < ISIS 14725 (full
PS, partial MOE); the absolute plasma concentration bioavailability was measured in reference to intravenous dosing in the
rat and was estimated at 0.3, 1.2, 2.1, and 5.5%, respectively. The optimal oligonucleotide chemistry for improved permeability
and resulting bioavailability was the partially modified 3â² hemimer 2â²- O -MOE phosphorothioate oligonucleotide (ISIS 14725). Improved presystemic stability coupled with improved permeability were
likely responsible for the remarkable improvement in the oral bioavailability of this compound. |
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AbstractList | Three modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA were characterized
for their presystemic stability and oral bioavailability compared with a first-generation phosphorothioate oligodeoxynucleotide
(PS ODN), ISIS 2302. The three modified oligonucleotides contained 2â²- O -(2-methoxyethyl) (2â²- O -MOE) ribose sugar modifications on a portion, or on all of the nucleotides in the antisense sequence. In vitro metabolism
studies conducted in various gastrointestinal and digestive tissue preparations indicated substantial improvement in stability
of 2â²- O -MOE-modified oligonucleotides. In addition, in vivo presystemic stability of these oligonucleotides was monitored in rats
following intraduodenal administration. By 8 h after administration, only chain-shortened metabolites of the PS ODN were recovered
in the gastrointestinal contents. In contrast, approximately 50% of the 2â²- O -MOE ribose-modified (partial) compound remained intact (20-mer) by 8 h following administration. Both of the fully modified
compounds (2â²- O -MOE PO and PS) were completely stable with no measurable metabolites observed within 8 h of administration. The rank order
of bioavailability was ISIS 11159 (full PS, full MOE) < ISIS 2302 (PS ODN) < ISIS 16952 (full PO, full MOE) < ISIS 14725 (full
PS, partial MOE); the absolute plasma concentration bioavailability was measured in reference to intravenous dosing in the
rat and was estimated at 0.3, 1.2, 2.1, and 5.5%, respectively. The optimal oligonucleotide chemistry for improved permeability
and resulting bioavailability was the partially modified 3â² hemimer 2â²- O -MOE phosphorothioate oligonucleotide (ISIS 14725). Improved presystemic stability coupled with improved permeability were
likely responsible for the remarkable improvement in the oral bioavailability of this compound. |
Author | Richard S. Geary Oleg Khatsenko Keith Bunker Henri Sasmor Max Moore Todd Burckin Rosanne Crooke LoAnne Truong Arthur A. Levin |
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Snippet | Three modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA were characterized
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Title | Absolute Bioavailability of 2â²-O-(2-Methoxyethyl)-Modified Antisense Oligonucleotides following Intraduodenal Instillation in Rats |
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