title: Absolute bioavailability of 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides following intraduodenal instillation in rats.
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 2'-O-(2-methoxyethyl) (2'-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 2'-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 2'-O-MOE ribose-modified (partial) compound remained intact (20-mer) by 8 h following administration. Both of the fully modified compounds (2'-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 3' hemimer 2'-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.
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA. rgeary@isisph.com
authors.forename: R S
authors.initials: RS
authors.lastname: Geary
authors.forename: O
authors.initials: O
authors.lastname: Khatsenko
authors.forename: K
authors.initials: K
authors.lastname: Bunker
authors.forename: R
authors.initials: R
authors.lastname: Crooke
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.forename: T
authors.initials: T
authors.lastname: Burckin
authors.forename: L
authors.initials: L
authors.lastname: Truong
authors.forename: H
authors.initials: H
authors.lastname: Sasmor
authors.forename: A A
authors.initials: AA
authors.lastname: Levin
mesh_terms: D000818:Animals; D001682:Biological Availability; D004355:Drug Stability; D008297:Male; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D016376:Oligonucleotides, Antisense; D013873:Thionucleotides