Document 0672
 DOCN  M9490672
 TI    Pharmacokinetics of an antisense phosphorothioate oligodeoxynucleotide
       against rev from human immunodeficiency virus type 1 in the adult male
       rat following single injections and continuous infusion.
 DT    9411
 AU    Iversen PL; Mata J; Tracewell WG; Zon G; Department of Pharmacology,
       University of Nebraska Medical; Center, Omaha 68198-6260.
 SO    Antisense Res Dev. 1994 Spring;4(1):43-52. Unique Identifier : AIDSLINE
       MED/94339691
 AB    An antisense phosphorothioate oligodeoxynucleotide 27-mer complementary
       to the rev gene mRNA of the human immunodeficiency virus (HIV-1) was
       administered to rats through intravenous injections and subcutaneous
       infusions in order to investigate the disposition of this compound. In
       addition, nonlethal toxic responses of the rat were evaluated. A
       biphasic plasma clearance with t1/2 alpha of 20-25 min and t1/2 beta of
       27-41 hr was observed. Single doses ranging from 35 to 3257 micrograms
       were examined, and the plasma concentration and area under the plasma
       concentration-time curve (AUC) were found to be directly proportional to
       the dose. Continuous subcutaneous infusion of 50 mg over 28 days was
       also examined. The oligonucleotide is completely eliminated in the urine
       over 3 days. Electrophoretic analysis demonstrated that the excreted
       compound has the same mobility and UV-absorbance profile as the
       administered compound. Measurement of accumulation and distribution into
       tissues revealed unique tissue-specific rates and extent of
       oligonucleotide movement into and out of tissues. Results of the chronic
       infusion study suggest that uptake into tissue is not saturated, even
       after 28 days of infusion. Analysis of blood plasma from
       oligonucleotide-treated animals shows a possible transient elevation in
       levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT),
       and aspartate aminotransferase (AST), but not alkaline phosphatase (AP),
       gamma-glutamyltransferase (GT), and bilirubin. The data collectively
       support the potential utility of phosphorothioate oligonucleotides as
       therapeutic agents in vivo.
 DE    Alanine Aminotransferase/BLOOD  Alkaline Phosphatase/BLOOD  Animal
       Aspartate Aminotransferase/BLOOD  Base Sequence  Bilirubin/BLOOD
       Chromatography, High Pressure Liquid  Gene Expression Regulation, Viral
       *Genes, rev  HIV-1/*GENETICS  Injections, Intravenous  Injections,
       Subcutaneous  Lactate Dehydrogenase/BLOOD  Male  Molecular Sequence Data
       Oligonucleotides, Antisense/ADMINISTRATION & DOSAGE/
       *PHARMACOKINETICS/TOXICITY  Rats  Rats, Sprague-Dawley  RNA,
       Messenger/METABOLISM  Thionucleotides/ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS/  TOXICITY  Tissue Distribution  JOURNAL
       ARTICLE

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