Zhou Shufeng, Kestell Philip, Paxton James W
Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Drug Metab Rev. 2002 Nov;34(4):751-90. doi: 10.1081/dmr-120015693.
The novel anti-tumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was developed in the Auckland Cancer Society Research Center. Its pharmacokinetic properties have been investigated using both in vitro and in vivo models, and the resulting data extrapolated to patients. The metabolism of DMXAA has been extensively studied mainly using hepatic microsomes, which indicated that UGT1A9 and UGT2B7-catalyzed glucuronidation on its acetic acid side chain and to a lesser extent CYP1A2-catalyzed hydroxylation of the 6-methyl group are the major metabolic pathways, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid. The predominant metabolite in human urine (up to 60% of total dose) was identified as DMXAA-G, which was chemically reactive, undergoing hydrolysis, intramolecular rearrangement, and covalent binding to plasma proteins. In vivo formation of DMXAA-protein adducts were also observed in cancer patients receiving DMXAA treatment. The comparison of the in vitro human hepatic microsomal metabolism and inhibition of DMXA by UGT and/or CYP substrates with animal species indicated species differences. Renal microsomes from all animal species examined had glucuronidation activity for DMXAA, but lower than the liver. In vitro-in vivo extrapolations based on human microsomal data indicated a 7-fold underestimation of plasma clearance in patients. In contrast, allometric scaling using in vivo data from the mouse, rat, and rabbit predicted a plasma clearance of 3.5 mL/min/kg, similar to that observed in patients (3.7 mL/min/kg). Based on in vitro metabolic inhibition studies, it appears possible to predict the effects on the plasma kinetic profile of DMXAA of drugs such as diclofenac, which are mainly metabolized by UGT2B7. However, it did not appear possible to predict the effect of thalidomide on the pharmacokinetics of DMXAA in patients based on in vitro inhibition and animal studies. These data indicate that preclincial pharmacokinetic studies using both in vitro and in vivo models play an important but different role in predicting pharmacokinetics and drug interactions in patients.
新型抗肿瘤药物5,6 - 二甲基呫吨酮 - 4 - 乙酸（DMXAA）由奥克兰癌症协会研究中心研发。已使用体外和体内模型对其药代动力学特性进行了研究，并将所得数据外推至患者。DMXAA的代谢主要通过肝微粒体进行了广泛研究，结果表明UGT1A9和UGT2B7催化其乙酸侧链的葡萄糖醛酸化，以及程度较轻的CYP1A2催化6 - 甲基的羟基化是主要代谢途径，产生DMXAA酰基葡萄糖醛酸（DMXAA - G）和6 - 羟甲基 - 5 - 甲基呫吨酮 - 4 - 乙酸。人尿中的主要代谢产物（高达总剂量的60%）被鉴定为DMXAA - G，它具有化学反应性，会发生水解、分子内重排以及与血浆蛋白的共价结合。在接受DMXAA治疗的癌症患者中也观察到了体内DMXAA - 蛋白质加合物的形成。体外人肝微粒体代谢以及UGT和/或CYP底物对DMXA的抑制作用与动物物种的比较表明存在物种差异。所检查的所有动物物种的肾微粒体对DMXAA均具有葡萄糖醛酸化活性，但低于肝脏。基于人微粒体数据的体外 - 体内外推表明患者的血浆清除率被低估了7倍。相比之下，使用小鼠、大鼠和兔子的体内数据进行的异速生长标度预测血浆清除率为3.5 mL/（min·kg），与患者中观察到的结果相似（3.7 mL/（min·kg））。基于体外代谢抑制研究，似乎有可能预测双氯芬酸等主要由UGT2B7代谢的药物对DMXAA血浆动力学曲线的影响。然而，基于体外抑制和动物研究，似乎无法预测沙利度胺对患者中DMXAA药代动力学的影响。这些数据表明，使用体外和体内模型进行的临床前药代动力学研究在预测患者的药代动力学和药物相互作用方面发挥着重要但不同的作用。
