DISPOSITION OF THE C-14-LABELED PHOSPHOROTHIOATE OLIGONUCLEOTIDE ISIS2105 AFTER INTRAVENOUS ADMINISTRATION TO RATS

5'-TTGCTTCCATCTTCCTCGTC-3' (ISIS 2105) is a phosphorothioate oligodeox ynucleotide currently being evaluated as an intralesional antiviral dr ug for the treatment of genital warts that are caused by the human pap illomavirus. ISIS 2105, labeled with C-14 (at the carbon-2 position of thymine) was administered as a single i.v. injection (3.6 mg/kg) to f emale Sprague-Dawley rats to assess the disposition of the drug. After i.v. administration of [C-14]2105, blood radioactivity disappeared in a multiexponential manner with the half-lives of the phases equal to 0.4, 1.9, 7.1 and 5.1 hr. The initial volume of distribution was 22 ml and the postdistribution volume of distribution was 1076 ml, which in dicated an extensive distribution of radioactivity. The apparent blood clearance was 14.7 ml/hr. The radioactivity in the expired air accoun ted for 51% of the administered dose over the 10-day period. Urinary a nd fecal radioactivity accounted for 15% and 5% of the administered do se, respectively. The major sites of radioactivity uptake were the liv er (up to 22.6% of the dose), kidneys (renal cortex, up to 14% of the dose), bone marrow (up to 14% of the dose), skin (up to 13% of the dos e) and skeletal muscle (up to 9% of the dose). Other tissues contained approximately 1% or less of the dose. The overall recovery of radioac tivity 10 days postdosing was 95.1 +/- 7.5% (mean +/- S.D.) of the adm inistered single dose. The radioactivity in the blood was almost compl etely in the plasma during the course of the study. In the plasma, the radioactivity was extensively bound to proteins, as assessed by size- exclusion high-performance liquid chromatography (HPLC), in samples up to 8 hr postdosing. Retention data on size-exclusion HPLC and in vitr o incubations using purified proteins suggested that the plasma protei ns that bound [C-14]2105 were albumin and alpha2-macroglobulin. The co mplex formed between the plasma proteins and [C-14]2105-derived radioa ctivity was dissociated on anion-exchange HPLC to indicate that the gr eat majority of plasma radioactivity coeluted with intact [C-14]2105 i n samples that contained sufficient radioactivity for analysis. There was a time-dependent decrease in the proportion of hepatic and renal r adioactivity that coeluted with the intact [C-14]2105 during the cours e of the study. The urine did not contain radioactivity that eluted wi th intact [C-14]2105 on anion-exchange HPLC.