Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats

PA Cossum, H Sasmor, D Dellinger, L Truong, L Cummins, SR Owens, PM Markham, JP Shea and S Crooke

Isis Pharmaceuticals, Inc., Carlsbad, California.

5'-TTGCTTCCATCTTCCTCGTC-3' (ISIS 2105) is a phosphorothioate oligodeoxynucleotide currently being evaluated as an intralesional antiviral drug for the treatment of genital warts that are caused by the human papillomavirus. ISIS 2105, labeled with 14C (at the carbon-2 position of thymine) was administered as a single i.v. injection (3.6 mg/kg) to female Sprague-Dawley rats to assess the disposition of the drug. After i.v. administration of [14C]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 indicated an extensive distribution of radioactivity. The apparent blood clearance was 14.7 ml/hr. The radioactivity in the expired air accounted for 51% of the administered dose over the 10-day period. Urinary and fecal radioactivity accounted for 15% and 5% of the administered dose, respectively. The major sites of radioactivity uptake were the liver (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 dose) and skeletal muscle (up to 9% of the dose). Other tissues contained approximately 1% or less of the dose. The overall recovery of radioactivity 10 days postdosing was 95.1 +/- 7.5% (mean +/- S.D.) of the administered single dose. The radioactivity in the blood was almost completely 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 vitro incubations using purified proteins suggested that the plasma proteins that bound [14C]2105 were albumin and alpha 2-macroglobulin. The complex formed between the plasma proteins and [14C]2105-derived radioactivity was dissociated on anion-exchange HPLC to indicate that the great majority of plasma radioactivity coeluted with intact [14C]2105 in samples that contained sufficient radioactivity for analysis. There was a time-dependent decrease in the proportion of hepatic and renal radioactivity that coeluted with the intact [14C]2105 during the course of the study. The urine did not contain radioactivity that eluted with intact [14C]2105 on anion-exchange HPLC.

Volume 267, Issue 3, pp. 1181-1190, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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