PHARMACOKINETICS OF A C-14-LABELED PHOSPHOROTHIOATE OLIGONUCLEOTIDE, ISIS-2105, AFTER INTRADERMAL ADMINISTRATION TO RATS

After intradermal administration of 3.7 mg/kg of C-14-labeled 5'-TTGCT TCCATCTTCCTCGTC-3'(C-14-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 blo od levels were achieved within 30 min. After the initial rapid phase o f absorption, a slower absorption phase ensued that resulted in more t han 95% of the dose being cleared from the injection site. Slow metabo lism of C-14-labeled ISIS 2105 occurred at the injection site. The rat e and characteristics of metabolism in the skin were similar to those observed in other tissues. Once absorbed, the pharmacokinetics, distri bution and metabolism of C-14-labeled ISIS 2105 after intradermal admi nistration were comparable to those after an i.v. dose. The distributi on and terminal half-lives were 0.5 and 53 hr, respectively. Levels of C-14-labeled ISIS 2105 in the blood were found in the plasma and the drug distributed broadly to all peripheral tissues; the liver, renal c ortex and bone marrow accumulated the highest levels of drug. The C-14 -labeled ISIS 2105 was eliminated principally by metabolism. Approxima tely 50% of the dose was found in expired air and 15% and 5% were foun d in urine and feces, respectively. No intact oligonucleotide was foun d in urine or feces at any time.