White R A, Workman P, Owen L N, Bleehen N M
Br J Cancer. 1979 Aug;40(2):284-94. doi: 10.1038/bjc.1979.177.
The hypoxic cell-radiosensitizing drug misonidazole (1-(2-nitroimidazol-1-yl)-3-methoxypropan -2 -ol, Ro 07-0582, MIS) was administered at a dose of 150 mg/kg i.v. to 6 dogs bearing spontaneous tumours, and the resulting tumour concentrations were measured to HPLC analysis. In 4 dogs it was possible to obtain serial biopsy specimens up to 5 h. With the exception of a brain tumour, the tumour concentrations ranged between 47% and 95% of the plasma concentration, most of the values falling within the range 50--70%. Concentrations in the brain tumour were markedly lower. Barbiturate anaesthesia was necessary for the removal of the serial biopsy specimens, and the effects of sodium pentobarbitone anaesthesia on the pharmacokinetics of MIS were investigated in 2 dogs. After barbiturate anaesthesia peak plasma concontrations were raised and the availability of MIS was increased, although the biological half-life remained unaltered. The metabolism of MIS to the O-demethylated metabolite, Ro 05-9963, was delayed initially. The concentrations of MIS AND Ro 05-9963 in cerebrospinal fluid were also recorded in these dogs; MIS concentrations were found to approach those of the plasma, whereas the metabolite concentrations were considerably lower (0--58% of the plasma concentration).
低氧细胞放射增敏药物米索硝唑（1-(2-硝基咪唑-1-基)-3-甲氧基丙-2-醇，Ro 07-0582，MIS）以150mg/kg的静脉注射剂量给予6只患有自发性肿瘤的犬，并通过高效液相色谱分析测定所得肿瘤浓度。在4只犬中，有可能获取长达5小时的系列活检标本。除脑肿瘤外，肿瘤浓度在血浆浓度的47%至95%之间，大多数值落在50%-70%的范围内。脑肿瘤中的浓度明显较低。获取系列活检标本需要巴比妥类麻醉，在2只犬中研究了戊巴比妥钠麻醉对米索硝唑药代动力学的影响。巴比妥类麻醉后，血浆峰值浓度升高，米索硝唑的可利用性增加，尽管生物半衰期保持不变。米索硝唑向O-去甲基代谢物Ro 05-9963的代谢最初延迟。还记录了这些犬脑脊液中米索硝唑和Ro 05-9963的浓度；发现米索硝唑浓度接近血浆浓度，而代谢物浓度则低得多（为血浆浓度的0%-58%）。
