PHARMACOKINETICS OF AN 'ANTISENSE' PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE AFTER SUBCUTANEOUS INFUSION IN MICE (MEETING ABSTRACT)

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

PHARMACOKINETICS OF AN 'ANTISENSE' PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE AFTER SUBCUTANEOUS INFUSION IN MICE (MEETING ABSTRACT)

Proc Annu Meet Am Assoc Cancer Res; 33:A3178 1992. Unique Identifier : AIDSLINE ICDB/92685713
Bigelow JC; Chrin LR; Mathews LA; McCormack JJ; Dept. of Pharmacology, Univ. of Vermont, Burlington, VT 05405

Abstract: NSC 624958 is a phosphorothioate oligodeoxynucleotide (S-ODN; 27-mer) with a base-sequence 'antisense' to the rev region of the HIV genome. Results of earlier pharmacokinetic studies, after iv administration to mice, suggested that continuous sc infusion might be an efficient approach to delivery of this drug. The majority of analytical work was done using ion-pair HPLC with a polymeric reversed-phase column and gradient elution with acetonitrile (22.5-30%) in phosphate buffer containing tetrabutylammonium phosphate; S-ODN was detected at 266 nm. Samples were processed by phenol extraction prior to HPLC analysis. S-ODN was administered sc to mice using osmotic minipumps; the estimated 'plateau' plasma concentration for an infusion at a rate of 100 ug/hr was approx 2 uM. Concentrations of S-ODN in liver and kidney were in the 3-6 uM range 24 hr after infusion at 80-100 ug/hr. As in our earlier study, after iv administration we observed very slow clearance of S-ODN from representative tissues, indicating a pharmacologically advantageous tissue persistence. Accumulation of S-ODN in tissues is clearly dose-related with approx proportional increases in tissue concentrations observed as the infusion rate was raised from 10 to 100 ug/hr. These studies suggest that sc infusion is an effective method of delivering S-ODNs to representative tissues.

Keywords: Animal Antiviral Agents/ADMINISTRATION & DOSAGE/PHARMACOLOGY/ *PHARMACOKINETICS Genome, Viral HIV/DRUG EFFECTS Infusions, Parenteral Kidney/METABOLISM Liver/METABOLISM Mice Oligonucleotides, Antisense/ADMINISTRATION & DOSAGE/PHARMACOLOGY/ *PHARMACOKINETICS Thionucleotides/ADMINISTRATION & DOSAGE/PHARMACOLOGY/ *PHARMACOKINETICS Tissue Distribution ABSTRACT
920830
M9281088

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