Pharmacokinetics of hypoxic cell radiosensitizers: a review

The comparative pharmacokinetics of various nitroimidazole radiosensitizers in different species are reviewed. Radiosensitization is dependent upon the tumor concentration at the time of radiotherapy, whereas host toxicity, including peripheral neuropathy, appears to be related to the tissue exposure or area under the curve (AUC). In contrast to in vitro structure-activity relationships, lipophilicity has a major effect on therapeutic ratio by influencing pharmacokinetics. Nitroimidazoles penetrate lipoid membranes by passive diffusion, the rate increasing with lipophilicity. Derivatives more hydrophilic than misonidazole (e.g., Ro 05-9963, SR-2508, and SR-2555) penetrate nervous tissues comparatively slowly, the corresponding AUC's are lower and they are generally less toxic. They are eliminated mainly by renal clearance, and also have shorter plasma t1/2's than misonidazole in the dog, but not in the mouse. The more lipophilic drugs are eliminated mainly by metabolism and their t1/2's are reduced by hepatic enzyme induction. Ro 07-0913, more lipophilic than misonidazole, has a shorter t1/2 in the mouse through more rapid metabolism to Ro 05-9963. Tumor penetration is independent of t1/2, at least over the range 1/2-20 hours, and also independent of partition coefficient over the range 0.026 to at least 1.5. The therapeutic ratio may be increased with drugs both more and less lipophilic than misonidazole. Most plasma data for intravenous radiosensitizers can be described by a two-compartment open model. But in the mouse, the kinetics of misonidazole are dose dependent with increasing apparent t1/2 and AUC at higher doses due to saturable Michaelis-Menten kinetics for metabolism.