Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion.

The pharmacokinetics and metabolism of an antisense oligonucleotide phosphorothioate (GEM91) were studied in cynomolgus monkeys following intravenous infusion. [35S]-Labeled GEM91 was administered to 12 monkeys by means of a 2-hour intravenous infusion at a dose of 4 mg/kg. Plasma pharmacokinetic analysis revealed that the maximum plasma concentration was 41.7 microg equivalents/ml, which was achieved in 2.13 hours. The plasma elimination half-life was 55.8 hours based on radioactivity levels. Urinary excretion represented the major pathway of elimination, with 70% of the administered dose excreted in urine over 240 hours. 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 [32p] on polyacrylamide gel electrophoresis showed the presence of both intact and degraded oligonucleotide in plasma, kidney, liver, spleen, and lymph nodes. 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.