Glover A, Chun H G, Kleinman L M, Cooney D A, Plowman J, Grieshaber C K, Malspeis L, Leyland-Jones B
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
Invest New Drugs. 1987;5(2):137-43. doi: 10.1007/BF00203538.
Merbarone was developed to clinical trial stage on the basis of its 'curative' activity against P388 and L1210 leukemias and moderate activity against B16 melanoma and M5076 sarcoma. Its activity appears to be schedule-dependent favoring a longer duration of administration. The mechanism of action of merbarone is not yet established but it does induce single strand breaks in DNA apparently without binding to DNA. The pharmacokinetic data in the dog indicate that clearance mechanisms may be saturable. Merbarone is hydroxylated at the 4' position in the rat, mouse and dog, and glucuronidated in the dog. Parent drug and the hydroxy metabolite are excreted in the urine. If saturable clearance mechanisms also pertain to man, this will mean that infusion rate (and therefore steady state concentrations reached) may be a significant factor in determining acute toxicity. Preclinical toxicology studies revealed that major target tissues are in the lymphoid organs, bone marrow, gastrointestinal tract and kidney. Some behavioral signs of reversible central nervous system toxicity were observed. Phase I trials have commenced using only a 5-day continuous intravenous infusion schedule based on the preclinical data. The pharmacokinetic information from these trials will be crucial for further clinical development of the compound, including selection of the optimal schedule(s) for phase II/III evaluation.
美巴龙因对P388和L1210白血病具有“治愈”活性，对B16黑色素瘤和M5076肉瘤具有中等活性而进入临床试验阶段。其活性似乎取决于给药方案，倾向于更长的给药持续时间。美巴龙的作用机制尚未明确，但它确实能诱导DNA单链断裂，且显然不与DNA结合。犬的药代动力学数据表明清除机制可能具有饱和性。在大鼠、小鼠和犬体内，美巴龙在4'位发生羟基化，在犬体内发生葡萄糖醛酸化。母体药物和羟基代谢物经尿液排泄。如果饱和清除机制在人体中也存在，这将意味着输注速率（以及因此达到的稳态浓度）可能是决定急性毒性的一个重要因素。临床前毒理学研究表明，主要靶组织位于淋巴器官、骨髓、胃肠道和肾脏。观察到一些可逆性中枢神经系统毒性的行为体征。根据临床前数据，一期试验仅采用了5天连续静脉输注方案。这些试验的药代动力学信息对于该化合物的进一步临床开发至关重要，包括选择用于二期/三期评估的最佳方案。
