Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate
Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate
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DOI：
10.1158/1078-0432.ccr-0518-03
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发表时间：
2004-02-15
影响因子：
11.5
通讯作者：
Bibby, MC
中科院分区：
文献类型：
--
作者：
Kirwan, IG;Loadman, PM;Bibby, MC
目的：考布他汀A4磷酸盐（CA 4P）及其结构类似物考布他汀A1磷酸盐（CA 1 P）是可溶性前药，能够与微管蛋白相互作用并导致肿瘤内的快速血管关闭。CA 4P已完成I期临床试验，但最近的临床前研究表明，CA 1 P在相同剂量下显示出比考布他汀A4（CA 4）类似物更大的抗肿瘤作用。实验设计：携带MAC 29肿瘤的NMRI小鼠接受治疗剂量为150 μ g/kg的CA 4P或CA 1 P注射mg.kg，并通过灵敏和特异的液相色谱/质谱法分析了这两种化合物及其代谢产物的概况。这两种化合物的代谢特征都很复杂，在血浆中检测到多达14种考布他汀A1（CA 1）代谢产物。其中许多代谢物已通过液相色谱/质谱法鉴别。然而，最初的研究集中在活性成分CA 4和CA 1上，其中CA 4的血浆和肿瘤曲线下面积分别为18.4和60.1 mug.h.ml g. h. ml（-1），CA 1的血浆和肿瘤曲线下面积分别为10.4和13.1 μ g. h. ml（-1）。两种化合物的体外代谢比较强烈提示CA 1代谢为比CA 4更具活性的物质。结论：尽管体外研究表明肿瘤特异性前药去磷酸化的速率不同可能解释了这些药代动力学特征的差异，但CA 1的抗肿瘤活性的提高和药代动力学特征的改变可能是由于形成了更具活性的代谢产物。
Purpose: Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity.Experimental Design: NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg.kg(-1), and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method.Results: The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 mug.h.ml(-1) for CA4, and 10.4 and 13.1 mug.h.ml(-1) for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4.Conclusions: Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.