Modulation of the pharmacokinetics of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice by thalidomide
Modulation of the pharmacokinetics of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice by thalidomide
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DOI：
10.1007/s002800000131
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发表时间：
2000-08-01
影响因子：
3
通讯作者：
Ching, LM
中科院分区：
文献类型：
--
作者：
Kestell, P;Zhao, LL;Ching, LM
背景：5，6-二甲基黄原酮-4-醋酸(DMXAA)是目前正在进行临床试验的一种研究药物，它通过诱导细胞因子作用于肿瘤血管。沙利度胺是一种细胞因子产生的调节剂，联合应用可增强DMXAA对小鼠结肠癌38的抗肿瘤活性。我们希望确定沙利度胺改变DMXAA的药代动力学是否可以为这种增强提供解释。结果：沙利度胺联合给药显著延长了DMXAA在血浆(413mU/L)、肝脏(132mU/L)和脾(77mU/L)中的消除半衰期(t(1/2))，并显著增加了结肠癌38肿瘤组织中DMXAA的浓度(0.25~4.5h)。L-沙利度胺对DMXAA的消除作用大于D-沙利度胺或消旋体(P<；0.01)。联合应用沙利度胺使DMXAA在血浆、肝脏和脾中的浓度-时间曲线下面积(AUC)增加1.8倍，在肿瘤中增加3.0倍。服用沙利度胺和DMXAA的小鼠胆汁中含有的DMXAA的葡萄糖醛酸代谢物(DMXAA-G)比单独服用DMXAA的小鼠的胆汁中的含量要低得多。结论：葡萄糖糖醛酸化是DMXAA在小鼠体内的主要排泄途径。沙利度胺，很可能是L式的：通过改变葡萄糖醛酸化的速率来降低DMXAA从血浆、脾、肝脏和肿瘤中的消除速率。沙利度胺对DMXAA的清除减少可能导致肿瘤组织对药物暴露的选择性增加，为其增强抗肿瘤活性提供了基础。
Background: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an investigative drug currently in clinical trial, acts on tumour vasculature through the induction of cytokines. Coadministration of thalidomide, a modulator of cytokine production, potentiates the antitumour activity of DMXAA against the murine Colon 38 carcinoma in mice. We wished to determine whether alteration of the pharmacokinetics of DMXAA by thalidomide could provide an explanation for this potentiation. Results: Coadministration of thalidomide to Colon 38 tumour-bearing mice significantly (P < 0.05) increased the elimination half-life (t(1/2)) of DMXAA in plasma (413 mu mol/l), liver (132 mu mol/l), and spleen (77 mu mol/l), and significantly (P < 0.05) increased DMXAA concentrations in Colon 38 tumour tissue (0.25-4.5 h). L-Thalidomide had a greater effect on DMXAA elimination (P < 0.01) than did D-thalidomide or the racemate. Coadministration of thalidomide increased the area under the concentration-time curve (AUC) of DMXAA by 1.8-fold in plasma, liver and spleen, and by 3.0-fold in tumour. Bile from mice given thalidomide and DMXAA contained substantially lower amounts of the glucuronide metabolite of DMXAA (DMXAA-G) than did bile from mice given DMXAA alone. Conclusion: Glucuronidation is a major excretory pathway for DMXAA in the mouse. Thalidomide, probably as the L-form: decreases the rate of elimination of DMXAA from plasma, spleen, liver and tumour by altering the rate of glucuronidation. The reduction in the elimination of DMXAA by thalidomide may lead to a selective increase in exposure of tumour tissue to drug, providing a basis for its potentiation of antitumour activity.