IN-VIVO TOXICITY OF FOSCARNET AND ZIDOVUDINE GIVEN ALONE OR IN COMBINATION

The toxicities of foscarnet (PFA) and zidovudine (AZT) given alone or in combination have been investigated in mice. PFA administered at a d ose of 500 mg/kg/day and AZT at a dose of 400 mg/kg/day for 17 days ca used clear hematotoxicity and nephrotoxicity, Each drug alone showed l ittle hematotoxicity, but using a combination of both drugs significan tly and dramatically decreased RBC (similar to 50%), Hb (similar to 43 %), and hematocrit (similar to 43%) and increased platelets (similar t o 45%) on Day 11 of treatment. It seems that there is a synergistic or at least an additive effect between PFA and AZT in terms of red blood cell toxicity. Surprisingly, AZT significantly increased serum creati nine levels on Days 5 and 11 of treatment (up to 40% increase), wherea s PFA was less toxic (only similar to 17% increase on Day 5 of treatme nt). Using a combination of the two drugs, PFA seems to reduce the nep hrotoxic effect of AZT on Day 11 of treatment. None of the treatments had an effect on BUN, At a lower dose level of 340 mg PFA/kg/day and 2 70 mg AZT/kg/day for 15 days there was hematotoxicity (much less evide nt than that at the higher dose level), but no nephrotoxicity. Electro n microscopic examination of the renal cortex of animals from the expe riments testing the higher dose levels revealed a clear vacuolization in proximal tubules and necrosis of mitochondria in distal tubules. Th ese effects were more striking with the combination and less evident w ith PFA or AZT alone. In conclusion, even though we have used a high d ose of AZT, there was synergistic/additive hematotoxicity. The combina tion was less nephrotoxic, only on Day 11 of treatment, than either of these agents used alone although histopathology at the time of euthan ization, showed more severe damage. (C) 1996 Academic Press, Inc.