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

Abstract

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 (P TP) of sensitizers increased with increase in the octanol/water partition coefficient (P ow) up to approximately 0.3 and was almost unity (maximum) for sensitizers with their P ow 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 (P BP) of sensitizers increased with increase in the P ow, attaining a constant value of almost unity at P ow > 0.5 for non-fluorine sensitizers or at P ow > 1.5 for fluorine-modified sensitizers. The maximum brain-affinity factor ((F B, t) max=(C B,t) max/D s, where (C B,t) max and D s are the maximum intrabrain concentration and the administered dose of sensitizer, respectively) was proportional to the maximum tumor-affinity factor ((F T,t) max=(C T,t) max/D s, where (C T,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/LD 50/7 was parallel to the sensitizing activity measured by 1/D S,1.5 (D S,1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo). The therapeutic risk index defined by D s,1.5/LD 50/7 depended on the side-chain structures of sensitizers. The D B,1–5LD 50/7 values of KU-2285 and ethanidazole (SR-2508) were 1 3 that of misonidazole (MISO). The sensitizers with smaller D s,1.5/LD 50/7 values showed higher sensitizing activities as their tumor amities increased, without an increase in serious toxicity.