Pharmacokinetics and toxicity of the human immunodeficiency virus inhibitor 1-ethoxymethyl-6-phenylselenenyl-5-ethyluracil in rodents.
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)
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D015497:HIV-1; D008297:Male; D051379:Mice; D016566:Organoselenium Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
D000998:Antiviral Agents; D016566:Organoselenium Compounds; C091742:5-ethyl-1-(ethoxymethyl)-6-(phenylselenenyl)uracil; D014498:Uracil