In vivo stability, pharmacokinetics, and metabolism of a 'hybrid' oligonucleotide phosphorothioate in rats (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

In vivo stability, pharmacokinetics, and metabolism of a 'hybrid' oligonucleotide phosphorothioate in rats (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A2450 1995. Unique Identifier : AIDSLINE ICDB/95610224
Lu Z; Zhao H; Diasio RB; Habus I; Jiang Z; Agrawal S; Zhang R; Dept. of Pharmacol. and Toxicol., Univ. of Alabama, Birmingham,; AL 35294

Abstract: A 'hybrid' oligonucleotide phosphorothioate, containing segment of oligodeoxynucleotide phosphorothioate flanked at 5'- and 3'-end by 2'-o-methyl oligoribonucleotide phosphorothioates, is found to be more active as anti-HIV agent than their oligodeoxynucleotide phosphorothioate counterpart. In the present study, pharmacokinetics and metabolism of this 'hybrid' oligonucleotide were determined in rats after iv bolus administration of 35S-radiolabeled compound at a dose of 30 mg/kg. Plasma disappearance curves for this oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr. The majority of radioactivity in plasma was present as intact compound. Urinary excretion represented the major pathway of elimination of this oligonucleotide, with 21.98 +/- 3.21% of the administered dose excreted within 24 hr and 38.13 +/- 2.99% over 240 hr post dosing. HPLC analysis showed that the majority of radioactivity in urine was degradative products with lower molecular weights but intact form was also detected. Fecal excretion was a minor pathway of elimination. A wide tissue distribution was observed with the chemical forms of radioactivity in most tissues being intact compound. Although it has a similar tissue distribution pattern compared to oligodeoxynucleotide phosphorothioate containing same sequence, the 'hybrid' oligonucleotide is more stable in vivo which may be important in development of antisense oligonucleotides as therapeutic agents.

Keywords: Animal Antineoplastic Agents/CHEMISTRY/*PHARMACOKINETICS Antiviral Agents/CHEMISTRY/*PHARMACOKINETICS HIV/DRUG EFFECTS Metabolic Clearance Rate Oligonucleotides/CHEMISTRY/*PHARMACOKINETICS Oligonucleotides, Antisense/CHEMISTRY/PHARMACOKINETICS Rats Structure-Activity Relationship ABSTRACT
951030
M95A0968

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