       Document 0065
 DOCN  M95B0065
 TI    Inhibition of human immunodeficiency virus type 1 replication by
       7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo
       metabolite of oltipraz.
 DT    9511
 AU    Prochaska HJ; Bornmann WG; Baron P; Polsky B; Molecular Pharmacology and
       Therapeutics Program, Memorial; Sloan-Kettering Cancer Center, New York,
       New York 10021, USA.
 SO    Mol Pharmacol. 1995 Jul;48(1):15-20. Unique Identifier : AIDSLINE
       MED/95349536
 AB    Oltipraz, an inhibitor of human immunodeficiency virus type 1
       replication in vitro (ED50 approximately 10 microM), undergoes extensive
       metabolism in vivo. Most of the orally administered drug undergoes
       opening of the dithiolethione ring, reduction, recyclization, and
       methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine
       (metabolite III). We report here that metabolite III inhibits viral
       replication in vitro (ED50 approximately 25 microM) in acutely infected
       H9 and CEM T cell lymphoma cell lines. Although both metabolite III and
       oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated
       viral replication in the chronically infected U1 promonocytic leukemia
       cell line, only metabolite III was able to inhibit
       phorbol-12-myristate-13-acetate-stimulated viral replication in
       chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2
       cells suggest that oltipraz inhibits an early stage of the viral life
       cycle, whereas metabolite III affects human immunodeficiency virus type
       1 replication at a step distal to viral integration. This is consistent
       with the finding that oltipraz inhibits reverse transcriptase, whereas
       metabolite III does not. Although the mean ED50 for metabolite III in
       acutely infected peripheral blood mononuclear cells was 18 microM, the
       ED50 was below 5 microM in three of eight independent experiments.
       Studies of metabolite III in combination with oltipraz in acutely
       infected peripheral blood mononuclear cells demonstrated significant
       antiviral synergy. These results raise the possibility that the in vitro
       potency of oltipraz may underestimate its antiretroviral activity in
       vivo. Based on these results, the pharmacokinetics of oltipraz and
       metabolite III will be compared with the pharmacodynamic effects of
       orally administered oltipraz in a forthcoming phase I/II trial of
       oltipraz in patients with p24 antigenemia.
 DE    Antiviral Agents/*PHARMACOLOGY  Cell Line  Human  HIV-1/*DRUG
       EFFECTS/ENZYMOLOGY/PHYSIOLOGY  Pyrazines/*METABOLISM/*PHARMACOLOGY
       Reverse Transcriptase/ANTAGONISTS & INHIB  Support, Non-U.S. Gov't
       Support, U.S. Gov't, P.H.S.  Tumor Cells, Cultured  Virus
       Replication/*DRUG EFFECTS  JOURNAL ARTICLE

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

