Pharmacokinetics of a 14C-labeled phosphorothioate oligonucleotide, ISIS 2105, after intradermal administration to...

After intradermal administration of 3.7 mg/kg of 14C-labeled 5'-TTGCTTCCATCTTCCTCGTC-3' (14C-labeled ISIS 2105) to rats, a phosphorothioate oligodeoxynucleotide, absorption was rapid. Approximately 65% of the administered dose was absorbed within 1 hr after the dose and peak blood levels were achieved within 30 min. After the initial rapid phase of absorption, a slower absorption phase ensued that resulted in more than 95% of the dose being cleared from the injection site. Slow metabolism of 14C-labeled ISIS 2105 occurred at the injection site. The rate and characteristics of metabolism in the skin were similar to those observed in other tissues. Once absorbed, the pharmacokinetics, distribution and metabolism of 14C-labeled ISIS 2105 after intradermal administration were comparable to those after an i.v. dose. The distribution and terminal half-lives were 0.5 and 53 hr, respectively. Levels of 14C-labeled ISIS 2105 in the blood were found in the plasma and the drug distributed broadly to all peripheral tissues; the liver, renal cortex and bone marrow accumulated the highest levels of drug. The 14C-labeled ISIS 2105 was eliminated principally by metabolism. Approximately 50% of the dose was found in expired air and 15% and 5% were found in urine and feces, respectively. No intact oligonucleotide was found in urine or feces at any time.