       Document 0026
 DOCN  M9620026
 TI    Pharmacokinetics and toxicity of the human immunodeficiency virus
       inhibitor 1-ethoxymethyl-6-phenylselenenyl-5-ethyluracil in rodents.
 DT    9602
 AU    Ni L; Schinazi RF; Boudinot FD; Department of Pharmaceutics, College of
       Pharmacy, University of; Georgia, Athens 30602, USA.
 SO    Antiviral Res. 1995 May;27(1-2):39-47. Unique Identifier : AIDSLINE
       MED/96075693
 AB    1-(Ethoxymethyl)-6-(phenylselenenyl)-5-ethyluracil (E-EPSeU) has been
       shown to exhibit potent and selective activity against human
       immunodeficiency virus type 1 in vitro. The pharmacokinetics of E-EPSeU
       were characterized after intravenous administration of 5, 10 and 15
       mg/kg to rats. Plasma and urine concentrations of E-EPSeU were
       determined by HPLC. The plasma protein binding of E-EPSeU averaged 86
       +/- 4% and the blood: plasma concentration ratio was unity. E-EPSeU
       concentrations after the 5 mg/kg dose were too low to reliably
       characterize the pharmacokinetics. The pharmacokinetics of E-EPSeU were
       independent of dose over the range of 10-15 mg/kg. Plasma concentrations
       of E-EPSeU declined in a bi-exponential manner with terminal half-life
       of 0.45 +/- 0.12 h (mean +/- S.D.). The steady-state volume of
       distribution was 0.091 +/- 0.031 1/kg, suggesting the compound
       distributed primarily into blood. The systemic clearance (0.63 +/- 0.13
       1/h/kg) was moderate and limited, in part, by protein binding. No parent
       compound was detected in urine. E-EPSeU-related toxicities were observed
       at high doses. One rat, out of 5, died 4 h after 15 mg/kg of E-EPSeU was
       administered and two rats administered 20 and 25 mg/kg died within 1 h.
       Two mice, out of 5, administered 30 mg/kg/day of E-EPSeU
       intraperitoneally for 6 days died during the experiment, while
       significant loss of body weight was observed in the surviving mice.
       However, body weight of the surviving mice returned to control values
       within 2 weeks after E-EPSeU treatment was stopped.(ABSTRACT TRUNCATED
       AT 250 WORDS)
 DE    Animal  Antiviral Agents/*PHARMACOKINETICS/TOXICITY  Dose-Response
       Relationship, Drug  Female  HIV-1  Male  Mice  Organoselenium
       Compounds/BLOOD/*PHARMACOKINETICS/TOXICITY  Rats  Rats, Sprague-Dawley
       Support, U.S. Gov't, Non-P.H.S.  Uracil/*ANALOGS &
       DERIVATIVES/BLOOD/PHARMACOKINETICS/TOXICITY  JOURNAL ARTICLE

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

