Kestell P, Paxton J W, Rewcastle G W, Dunlop I, Baguley B C
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Cancer Chemother Pharmacol. 1999;43(4):323-30. doi: 10.1007/s002800050902.
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an experimental antitumour agent currently undergoing phase I clinical trial, has a maximum tolerated dose (MTD) in male BDF1 mice of 99 micromol/kg. We have found the male Sprague-Dawley rat and the New Zealand White rabbit to have greater tolerance to DMXAA, with MTDs being 990 and 330 micromol/kg, respectively. To investigate the causes of this difference, we measured plasma and urine DMXAA concentrations by high-performance liquid chromatography (HPLC) after single i.v. bolus injections of 99 and 990 micromol/kg in the rat and following a bolus dose of 99 micromol/kg and a 10-min infusion of 330 micromol/kg in the rabbit. Following administration of DMXAA at the MTD in the mouse, rat and rabbit the maximal concentrations were 600, 2,200 and 1,708 microM, respectively, whereas areas under the concentration-time curves were 2,400, 19,000 and 2,400 microMh, respectively, for unchanged DMXAA. Data obtained for mice and rabbits were satisfactorily fitted to a two-compartment model with Michaelis-Menten kinetics. DMXAA was highly bound to plasma proteins, with the highest degree of binding being found in the rabbit. A small proportion of the total dose (7.8%, 0.6% and 12.4%, respectively) was excreted unchanged in urine over 24 h. This proportion increased (to 11.6%, 3.5% and 72.4%, respectively) following alkaline hydrolysis, suggesting the presence of glucuronide metabolites. Examination of rat and mouse urine by HPLC revealed the presence of two metabolites, which were characterized by mass spectrometry and nuclear magnetic resonance to be the acyl glucuronide of DMXAA and 6-(hydroxymethyl)-5-methylxanthenone-4-acetic acid. Thus, both mice and rats metabolise DMXAA by similar pathways. The results demonstrate considerable interspecies variations in tolerance to DMXAA that cannot be explained by differences in pharmacokinetics.
5,6-二甲基呫吨酮-4-乙酸（DMXAA）是一种目前正在进行I期临床试验的实验性抗肿瘤药物，雄性BDF1小鼠对其最大耐受剂量（MTD）为99微摩尔/千克。我们发现雄性Sprague-Dawley大鼠和新西兰白兔对DMXAA的耐受性更强，其MTD分别为990和330微摩尔/千克。为了研究这种差异的原因，我们在大鼠单次静脉推注99和990微摩尔/千克后，以及在兔子静脉推注99微摩尔/千克并持续输注10分钟330微摩尔/千克后，通过高效液相色谱法（HPLC）测定了血浆和尿液中的DMXAA浓度。在小鼠、大鼠和兔子中以MTD给予DMXAA后，最大浓度分别为600、2200和1708微摩尔/升，而对于未变化的DMXAA，浓度-时间曲线下面积分别为2400、19000和2400微摩尔·小时。小鼠和兔子的数据令人满意地拟合到具有米氏动力学的二室模型。DMXAA与血浆蛋白高度结合，在兔子中结合程度最高。在24小时内，总剂量的一小部分（分别为7.8%、0.6%和12.4%）以未变化的形式从尿液中排出。碱性水解后，这一比例增加（分别增至11.6%、3.5%和72.4%），表明存在葡萄糖醛酸代谢物。通过HPLC对大鼠和小鼠尿液的检测显示存在两种代谢物，通过质谱和核磁共振鉴定为DMXAA的酰基葡萄糖醛酸和6-（羟甲基）-5-甲基呫吨酮-4-乙酸。因此，小鼠和大鼠通过相似的途径代谢DMXAA。结果表明，对DMXAA的耐受性存在相当大的种间差异，这无法用药物动力学的差异来解释。
