Antimalarial activity of a combination of 5-fluoroorotate and uridine in mice.
Malarial parasites, in contrast to mammalian cells, utilize orotic acid more efficiently than uracil or uridine. Recently, chloroquine-susceptible and chloroquine-resistant clones of Plasmodium falciparum were shown to be inhibited by 5-fluoroorotate, with a 50% inhibitory concentration of 6 nM in vitro. Mammalian cells were far less sensitive to 5-fluoroorotate, particularly in the presence of uridine. In this report, the antimalarial activity of 5-fluoroorotate was tested in vivo. Initially, levels of 5-fluoroorotate in plasma were determined in Swiss mice injected intraperitoneally with radioactive 5-fluoroorotate. On the basis of the pharmacokinetics profile, mice infected with Plasmodium yoelii were treated with 5-fluoroorotate at a dose of 0.2 or 5 mg/kg (body weight) every 4 h for 3 days. At the nontoxic dose of 0.2 mg/kg, the reduction in parasitemia was followed by a temporary resurgence of parasitemia. This second wave of parasitemia cleared without additional 5-fluoroorotate treatment. To radically eliminate P. yoelii from mice and avoid the second wave of parasitemia, a higher dose of 5 mg of 5-fluoroorotate per kg had to be used. In the absence of uridine, repeated doses of 5 mg/kg were toxic to mice, as judged by weight loss, diarrhea, decreased numbers of leukocytes, and increased mortality. However, in the presence of uridine, repeated doses of 5 mg/kg could be used for antimalarial chemotherapy without obvious toxicity. Mice cured with 5-fluoroorotate and uridine were immune to subsequent challenge with a potentially lethal inoculum of P. yoelii.
Gómez
Z M
ZM
Department of Biology, Catholic University of America, Washington, D.C. 20064.
Rathod
P K
PK
D000818:Animals; D004338:Drug Combinations; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D010967:Plasmodium yoelii; D014529:Uridine / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity
D004338:Drug Combinations; D009963:Orotic Acid; C001242:5-fluoroorotic acid; D014529:Uridine