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Titolo:
IN-VIVO STABILITY, DISPOSITION AND METABOLISM OF A HYBRID OLIGONUCLEOTIDE PHOSPHOROTHIOATE IN RATS
Autore:
ZHANG RW; LU ZH; ZHAO H; ZHANG XS; DIASIO RB; HABUS I; JIANG ZW; IYER RP; YU D; AGRAWAL S;
Indirizzi:
UNIV ALABAMA,DEPT PHARMACOL & TOXICOL BIRMINGHAM AL 35294 UNIV ALABAMA,DIV CLIN PHARMACOL BIRMINGHAM AL 35294 HYBRIDON INC WORCESTER MA 01605
Titolo Testata:
Biochemical pharmacology
fascicolo: 4, volume: 50, anno: 1995,
pagine: 545 - 556
SICI:
0006-2952(1995)50:4<545:ISDAMO>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN IMMUNODEFICIENCY VIRUS; CHRONICALLY INFECTED-CELLS; OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATES; ANTISENSE OLIGONUCLEOTIDES; PHARMACOKINETICS; EXPRESSION; INHIBITORS; BIODISTRIBUTION; REPLICATION; ANALOGS;
Keywords:
ANTISENSE OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE; BIOSTABILITY; HIV; PHARMACOKINETICS; METABOLISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
R.W. Zhang et al., "IN-VIVO STABILITY, DISPOSITION AND METABOLISM OF A HYBRID OLIGONUCLEOTIDE PHOSPHOROTHIOATE IN RATS", Biochemical pharmacology, 50(4), 1995, pp. 545-556

Abstract

Oligodeoxynucleotide phosphorothioates containing segments of 2'-O-methyloligoribonucleotide phosphorothioates at both 3'- and 5'-ends (hybrid oligonucleotide) have been shown to be potent antisense agents, Inthe present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the S-35-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotidecould be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 +/- 3.21% (mean +/- SD) of the administered dose excreted within 24 hr and38.13 +/- 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lowermolecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 +/-0.13% of the administered dose excreted over 24 hr and 6.74 +/- 0.40%over 240hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynudeotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo,which may be important in the development of antisense oligonucleotides as therapeutic agents.

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Documento generato il 26/09/20 alle ore 00:52:22