Document 0967
 DOCN  M95A0967
 TI    In vivo stability, pharmacokinetics, and metabolism of a 'hybrid'
       oligonucleotide phosphorothioate in rats (Meeting abstract).
 DT    9510
 AU    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
 SO    Proc Annu Meet Am Assoc Cancer Res; 36:A2450 1995. Unique Identifier :
       AIDSLINE ICDB/95610224
 AB    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.
 DE    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  MEETING ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).