Metabolism of paclitaxel in mice
Metabolism of paclitaxel in mice
复制标题
DOI：
10.1097/00001813-200303000-00003
复制
发表时间：
2003-03-01
影响因子：
2.3
通讯作者：
van Tellingen, O
中科院分区：
文献类型：
--
作者：
Bardelmeijer, HA;Oomen, IAM;van Tellingen, O
先前在人类和小鼠中进行的质量平衡研究表明，紫杉醇和已知代谢物（3'p-羟基紫杉醇、6α-羟基紫杉醇和3'p,6α-二羟基紫杉醇）的粪便和尿液回收并不完全。显然，这种差异是由其他未知代谢物的存在引起的。 Mdr1a/1b(-/-) 小鼠分泌非常少量的未变化紫杉醇。因此，我们使用这些接受静脉注射的小鼠。 [H-3]紫杉醇进一步研究紫杉醇的代谢命运。放射性标记的大部分（70%）通过粪便排出。通过乙醚萃取获得亲脂性样品，其中含有粪便样品中约 70% 的放射性。使用甲醇进一步萃取含有约30%放射性的含水残余物。亲脂性和水性样品的高效液相色谱 (HPLC) 色谱图分别显示了两种和五种推定的紫杉醇新代谢物。对含有大量放射性的 HPLC 级分进行串联质谱分析。鉴定出两种新的单羟基紫杉醇结构，它们可能是2m-羟基紫杉醇和19-羟基紫杉醇，这两种结构先前在大鼠中鉴定过。包括这些代谢物，大约 60% 的紫杉醇质量平衡可以被量化。
Previous mass balance studies in humans and mice have shown that the fecal and urinary recovery of paclitaxel and known metabolites (3'p-hydroxypaclitaxel, 6alpha-hydroxypaclitaxel and 3'p,6alpha-dihydroxypaclitaxel) was not complete. Obviously this discrepancy is caused by the existence of other yet unknown metabolites. Mdr1a/1b(-/-) mice excrete very low quantities of unchanged paclitaxel. We have therefore used these mice receiving i.v. [H-3]paclitaxel to further study the metabolic fate of paclitaxel. The major part of the radiolabel, being 70%, was excreted in the feces. A lipophilic sample, containing about 70% of the radioactivity present in the feces sample, was obtained by diethyl ether extraction. The aqueous residue containing about 30% of the radioactivity was further extracted using methanol. The high-performance liquid chromatography (HPLC) chromatograms of the lipophilic and aqueous sample revealed two and five putative new metabolites of paclitaxel, respectively. The HPLC fractions containing substantial amounts of radioactivity were subjected to tandem mass spectrometry. Two novel monohydroxylated paclitaxel structures were identified, which are probably 2m-hydroxypaclitaxel and 19-hydroxypaclitaxel, structures previously identified in rats. Including these metabolites, about 60% of the mass balance of paclitaxel could be quantified.