PHARMACOKINETICS AND METABOLISM OF AN OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE (GEM91(R)) IN CYNOMOLGUS MONKEYS FOLLOWING INTRAVENOUS-INFUSION

The pharmacokinetics and metabolism of an antisense oligonucleotide ph osphorothioate (GEM91(R)) were studied in cynomolgus monkeys following intravenous infusion. [S-35]-Labeled GEM91 was administered to 12 mon keys by means of a 2-hour intravenous infusion at a dose of 4 mg/kg. P lasma pharmacokinetic analysis revealed that the maximum plasma concen tration was 41.7 mu g equivalents/ml, which was achieved in 2.13 hours . The plasma elimination half-life was 55.8 hours based on radioactivi ty levels. Urinary excretion represented the major pathway of eliminat ion, with 70% of the administered dose excreted in urine over 240 hour s. The oligonucleotide was widely distributed to tissues. The highest concentrations were observed in the liver and kidney. Analysis of the extracted oligonucleotide following post-labeling with [P-32] on polya crylamide gel electrophoresis showed the presence of both intact and d egraded oligonucleotide in plasma, kidney, liver, spleen, and lymph no des. Based on the methods used for post-labeling (either 3'-end or 5'- end), different patterns of bands were observed on polyacrylamide gel electrophoresis, suggesting metabolic modification of the administered oligonucleotide.