The
2-nitroimidazole benznidazole (BENZO) has previously been shown to be an effective potentiator of the cytotoxicity of
CCNU in mice, at levels which are achievable in man. This enhancement is greater than that for normal tissues, resulting in a therapeutic gain. In this study BENZO has been given to 46 patients in oral doses of 4 mg/kg to 30 mg/kg, and
drug concentrations measured in plasma, urine,
tumor and normal brain by HPLC. The mean plasma t 1/2 was 12.8 +/- 0.5 h and plasma peak concentration and AUC0-infinity were linearly related to dose over the whole range. Approximately 60% of the
drug was bound to
plasma proteins and 6% excreted unchanged in urine. Mean
tumor/plasma ratios of 88% (range 54 to 122%) for 11
gliomas and 72% (range 46 to 103%) for 6 superficially accessible non-
brain tumors were obtained while that for normal brain was 69% (range 53 to 75%). Doses of more than 17 mg/kg BENZO produce changes in the plasma pharmacokinetics of
CCNU (130 mg/m2 p.o.), increasing the half life of active hydroxylated metabolites. In addition,
CCNU parent compound is present. This is not seen when
CCNU is given alone. Such changes may result in improved response rates as it is possible to achieve in man, plasma and
tumor levels of BENZO, which in the mouse model produce effective enhancement of the response to
CCNU. No evidence was seen that BENZO enhanced wither the acute gastrointestinal toxicity or the hematological toxicity of
CCNU over the dose range studied.