Biotransformation profiling of [14C]Ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS)

Comezglu, S. Nilgun, Ly, Van T., Zhang, Donglu , Humphreys, W. Griffith, Bonacorsi, Samuel J., Everett, Donald W., Cohen, Marvin B., Gan, Jinping, Beumer, Jan H., Beijnen, Jos H., Schellens, H. M. and Lappin, Graham (2009) Biotransformation profiling of [14C]Ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS). Drug Metabolism and Pharmacokinetics, 24 (6). pp. 511-522. ISSN 1347-4367

Full content URL: https://www.jstage.jst.go.jp/article/dmpk/24/6/24_...

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Abstract

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 14C detection could not be conducted due to the radiolytic instability of [14C]ixabepilone at a typical specific activity (generally 1-10 μCi/mg). However, [14C]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 [14C]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 [14C]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 [14C]ixabepilone following administration to humans.

Keywords:Ixabepilone, Ixempraâ„¢ cancer, metabolism, human, accelerator mass spectrometry (AMS), metabolite
Divisions:College of Science > School of Pharmacy
ID Code:7360
Deposited On:27 Feb 2013 17:17

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