Neurotoxicity with desmethylmisonidazole

Abstract

There are now underway many clinical trials of misonidazole as an hypoxic cell sensitizer in radiotherapy. Because of the risk of neurotoxicity the total dose which may be given has been limited and in most trials a total of 12 g per square metre of surface area is set as the maximum. This limitation has given further stimulus to the search for drugs which may have a better therapeutic ratio. A direct correlation has been found between the tissue exposure to misonidazole as indicated by the area under the curve of plasma concentration with time and the incidence of neurotoxicity (Dische et al., 1979). Much attention has been concentrated on those nitroimidazoles which have a lower lipophilicity than misonidazole, for in animal studies these drugs show shorter halflives in plasma and lower concentrations in the central nervous system whilst similar concentrations are detected in tumours (Brown and Workman, 1980).