Co-administration of polyanions with a phosphorothioate oligodeoxynucleotide (CGP 69846A): a role for the scavenger receptor in its in vivo disposition.
The effects of co-administering polyanions on the pharmacokinetics of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A), and the role of scavenger receptors in its in vivo disposition, have been investigated. Following i.v. administration, CGP 69846A was rapidly cleared from the plasma and distributed amongst high (e.g. kidney, liver, spleen), low (e.g. skeletal muscle) and negligible (e.g. brain) accumulating tissues. In addition it was shown that: 1) dextran sulphate co-administration has a dose-dependent effect on the disposition of CGP 69846A; 2) CGP 69846A undergoes renal filtration and renal accumulation largely results from tubular reabsorption; 3) cross-inhibition studies are consistent with CGP 69846A being recognized by scavenger receptors in vitro and in vivo; and 4) the scavenger receptor may be an important determinant for the in vivo disposition of CGP 69846A in mice. These studies contribute toward an increased understanding of the mechanism underlying the pharmacokinetic behaviour of phosphorothioate oligodeoxynucleotides.
Novartis Horsham Research Centre, Horsham, West Sussex, UK. alan.steward@pharma.novartis.com
A
A
Steward
R A
RA
Christian
K O
KO
Hamilton
P L
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Nicklin
D000818:Animals; D001345:Autoradiography; D002460:Cell Line; D016264:Dextran Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013873:Thionucleotides / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013873:Thionucleotides; C099587:ISIS 5132; D016264:Dextran Sulfate