Workman P, White R A, Talbot K
Cancer Chemother Pharmacol. 1986;16(1):1-8. doi: 10.1007/BF00255278.
Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 micrograms/ml in mice, while 25 mg/kg gave peak plasma concentrations of 27 micrograms/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t1/2 values were 1.4-2 h in mice and 2.5-4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%-90%, while brain: plasma ratios were lower, at 37%-50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%-29%, of which 16%-25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new 'mixed-function' sensitizers.
尽管15年来它一直备受关注，最初是作为一种细胞毒性剂，最近又作为一种放射增敏剂，但关于CB 1954（2,4 - 二硝基 - 5 - 氮丙啶基苯甲酰胺）的药代动力学信息却非常少。我们开发了一种针对该药物及其代谢物的快速高效液相色谱分析法，并将其应用于详细研究CB 1954在小鼠和犬体内的药代动力学。静脉注射时，50 mg/kg的剂量使小鼠的血药峰浓度达到100微克/毫升，而25 mg/kg的剂量使犬的血浆峰浓度达到27微克/毫升。小鼠腹腔注射途径和犬口服途径的峰浓度分别比静脉注射低3至5倍，生物利用度分别为85%和40%。消除半衰期在小鼠中为1.4 - 2小时，在犬中为2.5 - 4小时，且与给药途径无关。血浆蛋白结合率为57%，但在小鼠体内组织穿透力总体良好。肿瘤与血浆的比值为50% - 90%，而脑与血浆的比值较低，为37% - 50%。在小鼠尿液中鉴定并定量了母体药物和几种代谢物，总回收率为24% - 29%，其中16% - 25%为母体药物。代谢物也存在于循环系统和组织中。在小鼠中重复给药或给予保护剂苯基AIC时，药代动力学未见变化。苯巴比妥预处理使消除半衰期略有缩短，主要是通过加速氮丙啶环的去除。别嘌呤醇增加了5 - 氨基硝基还原产物的血药水平。这些研究为解释CB 1954的抗肿瘤活性和毒性以及开发新的“混合功能”增敏剂提供了药代动力学依据。
