COADMINISTRATION OF POLYANIONS WITH A PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE (CGP 69846A) - A ROLE FOR THE SCAVENGER RECEPTOR IN ITS IN-VIVODISPOSITION

The effects of co administering polyanions on the pharmacokinetics of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A), and the r ole of scavenger receptors in its in vivo disposition, have been inves tigated. Following i.v. administration, CGP 69846A was rapidly cleared from the plasma and distributed amongst high (e.g. kidney, liver, spl een), low (e.g. skeletal muscle) and negligible (e.g. brain) accumulat ing tissues. In addition it was shown that: 1) dextran sulphate co-adm inistration has a dose dependent effect on the disposition of CGP 6984 6A; 2) CGP 69846A undergoes renal filtration and renal accumulation la rgely results from tubular reabsorption; 3) cross inhibition studies a re consistent with CGP 69846A being recognized by scavenger receptors in vitro and in vivo; and 4) the scavenger receptor may be an importan t 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 oligodeo xynucleotides. BIOCHEM PHARMACOL 56;4:509-516, 1998. (C) 1998 Elsevier Science Inc.