Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
Drug Metab Pharmacokinet. 2009;24(6):511-22. doi: 10.2133/dmpk.24.511.
Ixabepilone (BMS-247550, Ixempra is a semi-synthetic analog of the natural product epothilone B and marketed for its use in the treatment of cancer. A conventional human ADME study using decay counting methods for (14)C detection could not be conducted due to the radiolytic instability of [(14)C]ixabepilone at a typical specific activity (generally 1-10 microCi/mg). However, [(14)C]ixabepilone was sufficiently stable at low specific activity (1-2 nCi/mg). These low levels required the use of accelerator mass spectrometry (AMS) for radioactivity detection. The metabolic fate of this compound was investigated in eight patients following single intravenous doses of [(14)C]ixabepilone (70 mg, 80 nCi; specific activity: 1.14 nCi/mg). Metabolite profiles in pooled urine, feces and plasma samples were determined by HPLC-AMS analysis. The major radioactive component in urine and plasma was [(14)C]ixabepilone. Feces had a small amount of ixabepilone. There were numerous other drug-related components in both urine and fecal extracts (each <6% of the administered dose). LC/MS analysis of plasma, urine and feces samples showed the presence of three degradants of ixabepilone and several oxidative metabolites (M+16, M+14 and M-2 metabolites). This study demonstrates the utility of AMS in investigating the metabolite and excretion profiles of [(14)C]ixabepilone following administration to humans.
依沙匹隆（BMS-247550，Ixempra）是天然产物埃博霉素 B 的半合成类似物，因其在癌症治疗中的应用而上市。由于典型比活度（通常为 1-10 微 Ci/mg）下的 [(14)C]依沙匹隆的放射分解不稳定性，无法使用衰变计数法进行常规的人类 ADME 研究。然而，[(14)C]依沙匹隆在低比活度（1-2 nCi/mg）下足够稳定。这些低水平需要使用加速器质谱 (AMS) 进行放射性检测。在 8 名患者单次静脉注射 [(14)C]依沙匹隆（70mg，80nCi；比活度：1.14nCi/mg）后，研究了该化合物的代谢命运。通过 HPLC-AMS 分析确定了合并尿、粪便和血浆样品中的代谢物谱。尿液和血浆中的主要放射性成分是 [(14)C]依沙匹隆。粪便中含有少量依沙匹隆。尿液和粪便提取物中都有许多其他与药物相关的成分（每个成分 <6%的给药剂量）。对血浆、尿液和粪便样品的 LC/MS 分析表明，依沙匹隆有三种降解产物和几种氧化代谢物（M+16、M+14 和 M-2 代谢物）。本研究证明了 AMS 在研究 [(14)C]依沙匹隆在人类给药后的代谢物和排泄谱中的应用。
