Structure-pharmacokinetic relationships for misonidazole analogues in mice

We have compared the mouse pharmacokinetics of six analogues of the hypoxic cell sensitizer misonidazole (MISO). The analogues were all uncharged and similar in redox potential, but widely different in octanol-water partition coefficient (range 0.026-1.5). Lipophilic analogues were cleared mainly by metabolism and non-linear elimination kinetics were seen at high doses. Hydrophilic analogues, including desmethylmisonidazole, SR-2508, and SR-2555, were removed principally by renal clearance exhibiting linear elimination kinetics. Lipophilic analogues were cleared more rapidly after hepatic microsomal enzyme induction by phenobarbitone, whereas the kinetics of hydrophilic analogues were unaffected. Low-dose clearance was similar for most of the analogues. But the hydrophilic SR-2555 was cleared twice as quickly as MISO, and the lipophilic Ro 07-0913 seven times faster than MISO. Plasma protein binding was low for all the analogues. The significance of these results for the predictive value of the mouse as a model for man is discussed.