Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole.

Ten 2-nitroimidazole radiosensitizers of electron affinity equal to that of misonidazole, but differing in their octanol:water partition coefficient over a 100-fold range, were chosen to examine the effect of lipophilicity on the pharmacokinetics of these drugs in BALB/c mice bearing EMT6 tumors. Plasma, tumor, and brain concentrations were assayed, using high-performance liquid chromatography (HPLC), as a function of time after a single ip injection of each drug. It was found that peak concentrations in the tumor declined with decreasing lipophilicity (decreasing partition coefficient), but that this was due to declining peak plasma concentrations resulting from slower drug absorption and could be overcome by iv injection. The tumor/plasma ratio, once sufficient time had elapsed for it to reach its equilibrium value, was independent of partition coefficient (P) over the range 0.026 to 1.5 but showed a 50% reduction in this ratio for the most hydrophilic compound studied (P = 0.014). (This compound was also the one drug in the series which was significantly poorer than misonidazole in its radiosensitization as a function of drug concentration.) The brain/ plasma ratio, on the other hand, showed a marked dependence on lipophilicity. For misonidazole and more lipophilic compounds, the brain/plasma ratio was 1.0, but as the lipophilicity decreased below that of misonidazole, the compounds showed an increasing difficulty in penetration into the brain, and brain/plasma levels of less than 0.1 were found for the most hydrophilic drugs. These low brain/plasma ratios correlated with an increased acute LDs0 of the drugs. Bilateral nephrectomy was used to increase the apparent plasma half-life of SR-2508 from 0.8 to 15 hr. This change, however, did not affect the tumor/brain ratio of approximately 10 for this drug. The significance of these pharmacokinetic data is discussed in terms of the development of a radiosensitizer superior to misonidazole for clinical use.