Pharmacokinetics and toxicity of the human immunodeficiency virus inhibitor 1-ethoxymethyl-6-phenylselenenyl-5-ethyluracil in rodents

Abstract

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 l/kg, suggesting the compound distributed primarily into blood. The systemic clearance (0.63 ± 0.13 l/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. While toxicities were observed after high doses of E-EPSeU, effective anti-HIV E-EPSeU plasma concentrations were achieved without toxicities by administering lower doses.