Meeting of the minds on mercury.

-Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its 0-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS. this apparent advantage was offset by peak tumour levels 5000 or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-059963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization pro duced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0-5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified.