Assessment of the antimalarial potential of tetraoxane WR 148999

The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synerg istic with chloroquine, quinine, mefloquine, and artemisinin against both D 6 and W2 clones of Plasmodium falciparum. In consideration of the contrasti ng antagonism between artemisinin and chloroquine, these drug combination d ata imply that WR 148999 and artemisinin may not share a common mechanism o f action. For Plasmodium berghei-infected mice given oral, subcutaneous, an d intraperitoneal doses of WR 148999 ranging from 2 to 1024 mg/kg in the Th ompson test, median survival times were 8.8, 11.8, and 27.5 days, respectiv ely, compared to 8 days for control animals. Using subcutaneous administrat ion, WR 148999 had a considerably longer duration of action than did artemi sinin against P. berghei. WR 148999 did not significantly inhibit cytochrom e P450 isozymes CYP 2C9, 2C19, 2D6, 2E1, or 3A4 (IC50 >500 muM) but did inh ibit CYP 1A2 with an IC50 value of 36 muM, suggesting that WR 148999 may be metabolized by the latter CYP isozyme. These results combined with previou s observations that formulation strategies and incorporation of polar funct ional groups in a series of WR 148999 analogs both failed to enhance tetrao xane oral antimalarial activity suggest that oral bioavailability of tetrao xane WR 148999 is more likely a function of extensive first-pass metabolism rather than solubility-limited dissolution.