Fluorine modification of nitroazole radiosensitizers for the enhancement of sensitizing activity with lowering toxicity: a pharmacokinetic characterization.

Pharmacokinetic characterization of various nitroazole radiosensitizers was carried out to clarify the effect of fluorine modification of the side-chain groups on the sensitizing activity and the acute toxicity. The in vivo tumor/plasma partition coefficient (PTP) of sensitizers increased with increase in the octanol/water partition coefficient (Pow) up to approximately 0.3 and was almost unity (maximum) for sensitizers with their Pow values larger than approximately 0.3. This relationship was observed commonly for all types of sensitizers independent of the fluorine modification. The in vivo brain/plasma partition coefficient (PBP) of sensitizers increased with increase in the Pow, attaining a constant value of almost unity at Pow greater than 0.5 for non-fluorine sensitizers or at Pow greater than 1.5 for fluorine-modified sensitizers. The maximum brain-affinity factor ((FB,t)max = (CB,t)max/Ds, where (CB,t)max and Ds are the maximum intrabrain concentration and the administered dose of sensitizer, respectively) was proportional to the maximum tumor-affinity factor ((FT,t)max = (CT,t)max/Ds, where (CT,t)max is the maximum intratumor concentration of sensitizer), depending on the side-chain structure of the sensitizer. A series of non-fluorine and fluorine-modified nitroazole derivatives, including N-(2'-hydroxyethyl)-2,2-difluoro-3-(3''-nitro-1'-triazolyl)propionamide (KU-2285), gave a smaller brain to tumor ratio of approximately 1/7. The toxicity index defined by 1/LD50/7 was parallel to the sensitizing activity measured by 1/DS,1.5 (DS,1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo). The therapeutic risk index defined by Ds,1.5/LD50/7 depended on the side-chain structures of sensitizers. The DB,1-5LD50-/7 values of KU-2285 and ethanidazole (SR-2508) were 1/3 that of misonidazole (MISO). The sensitizers were smaller Ds,1.5/LD50/7 values showed higher sensitizing activities as their tumor affinities increased, without an increase in serious toxicity.