Efficacy of continuous zidovudine infusion at early stages of retroviral infection in mice.
We studied the pharmacokinetics of zidovudine (ZDV) in mice after twice-daily s.c. bolus injections and during continuous infusion with s.c. ALZET mini-osmotic pumps. We also compared the antiretroviral efficacy of these two modes of administration against Friend leukemia virus (FLV) infection. Mice were infected by retro-orbital inoculation of about 50 focus-forming units (ffu) of FLV, and treatment was started 1 or 4 h later with ZDV at 40 mg/kg/day for 5 days. Efficacy was evaluated in terms of spleen weight and/or virus titer (spleen focus assay) on day 21 in comparison with untreated infected mice. In a separate experiment, survival time after infection was also monitored over a 140-day period. Plasma concentrations of ZDV were determined by means of high-performance liquid chromatography. Following bolus administration, the peak plasma ZDV concentration (30.5 mg/ml) was reached within 10 min, and elimination was rapid (mean half-life, 0.7 h). During the continuous infusion, the mean concentration was constant at about 1.2 mg/ml. After 5 days of treatment, continuous ZDV infusion consistently inhibited virus-induced splenomegaly by more than 97%; bolus injections were less effective with inhibition ranging from 13 to 98%. These results suggest that moderate constant levels of ZDV have greater antiretroviral efficacy than intermittent high concentrations.
Sinet
M
M
Unité de Recherches U13 INSERM, Hôpital Claude Bernard, Paris, France.
Harcouet
L
L
Desforges
B
B
Colin
J N
JN
Farinotti
R
R
Pocidalo
J J
JJ
D000818:Animals; D004195:Disease Models, Animal; D005622:Friend murine leukemia virus / Q000502:physiology; D007942:Leukemia, Experimental / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012192:Retroviridae Infections / Q000188:drug therapy*; D014779:Virus Replication; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D015215:Zidovudine