A drug for improved radiosensitization in radiotherapy

Desmethylmisonidazole (DESMISO), the first metabolite of misonidazole (MISO), is about equal in efficiency to MISO as a radiosensitizer of hypoxic tumour cells. However DESMISO is reported to have a lower lipophilicity and a shorter half-life in dogs and mice which together should decrease the incidence of neurotoxicity observed in MISO therapy. Following the administration of 0.5g DESMISO/m2 or 0.5g MISO/m2 to three normal volunteers, after 1-2 h the average plasma DESMISO concentrations were 85, 82 and 72% of the total nitroimidazoles (DESMISO + MISO) when MISO was given. Subsequently the DESMISO levels fell more rapidly, with half-lives approximately half that observed for MISO. Doubling the dose of DESMISO appeared to double the plasma concentrations as has previously been observed with MISO. After administration of the 0.5g/m2 dose of DESMISO, 44, 55 and 59% of the dose was excreted in 24 hrs. When the dose was doubled, 50 and 52% was excreted. In contrast, after administration of MISO, 31, 23 and 34% was excreted either unchanged or as DESMISO. The results suggest that DESMISO might prove a more efficient drug for oral use as an hypoxic cell radiosensitizer in man than MISO. (U.K.)