Nitroimidazoles as modifiers of nitrosourea pharmacokinetics.

We have studied the effect of a number of nitroimidazole sensitizers of varying lipophilicity on the pharmacokinetics of CCNU in mice. It was found that the effectiveness of these compounds in producing pharmacokinetic effects correlated directly with their lipophilicity, viz. in the order: benznidazole (Benzo) greater than Ro07-1902 misonidazole greater than (MISO) greater than Ro05-9963. The effects of MISO on the pharmacokinetics of 4 nitrosoureas of differing lipophilicity were also investigated. The plasma clearances of CCNU, BCNU and MeCCNU (high lipophilicity) were slowed by MISO whereas that of chlorozotocin (Chlz) (low lipophilicity) was unaffected. Thus, it seems that for a pharmacokinetic interaction to occur between a nitroimidazole and a nitrosourea, both the modifier and the cytotoxic agent must have a requisite degree of lipophilicity. As the same requirement appears to hold for enhancement of tumor response, these data provide further evidence that pharmacokinetic modification plays a major role in chemosensitization.