Kirwan Ian G, Loadman Paul M, Swaine David J, Anthoney D Alan, Pettit George R, Lippert John W, Shnyder Steve D, Cooper Patricia A, Bibby Mike C
Cancer Research Unit, Tom Connors Cancer Research Centre, University of Bradford, Bradford, United Kingdom.
Clin Cancer Res. 2004 Feb 15;10(4):1446-53. doi: 10.1158/1078-0432.ccr-0518-03.
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.
NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg x kg(-1), and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method.
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 microg x h x ml(-1) for CA4, and 10.4 and 13.1 microg x h x 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.
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.
磷酸考布他汀A4（CA4P）及其结构类似物磷酸考布他汀A1（CA1P）是可溶性前体药物，能够与微管蛋白相互作用并导致肿瘤内血管迅速关闭。CA4P已完成I期临床试验，但最近的临床前研究表明，在同等剂量下，CA1P比考布他汀A4（CA4）类似物具有更强的抗肿瘤作用。因此，本研究的目的是比较这两种化合物的药代动力学和代谢情况，以确定药代动力学是否在它们的差异活性中起作用。
携带MAC29肿瘤的NMRI小鼠接受150 mg·kg⁻¹治疗剂量的CA4P或CA1P注射，通过灵敏且特异的液相色谱/质谱法分析这两种化合物及其代谢物的情况。
两种化合物的代谢情况都很复杂，血浆中检测到考布他汀A1（CA1）的代谢物多达14种。其中许多代谢物已通过液相色谱/质谱法鉴定出来。然而，初步研究集中在活性成分CA4和CA1上，CA4的血浆和肿瘤曲线下面积分别为18.4和60.1 μg·h·ml⁻¹，CA1的分别为10.4和13.1 μg·h·ml⁻¹。两种化合物的体外代谢比较强烈表明，CA1比CA4代谢为更具反应性的物质。
虽然体外研究表明肿瘤特异性前体药物去磷酸化速率的差异可能解释了这些药代动力学特征的不同，但CA1改善的抗肿瘤活性和改变的药代动力学特征可能是由于形成了更具反应性的代谢物。
