Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
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Biotransformation Profiling of [14C]Ixabepilone in Human Plasma, Urine and Feces Samples Using Accelerator Mass Spectrometry (AMS)
S. Nilgün ÇÖMEZOĞLUVan T. LYDonglu ZHANGW. Griffith HUMPHREYSSamuel J. BONACORSIDonald W. EVERETTMarvin B. COHENJinping GANJan H. BEUMERJos H. BEIJNENH. M. SCHELLENSGraham LAPPIN
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2009 Volume 24 Issue 6 Pages 511-522

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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.

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© 2009 by The Japanese Society for the Study of Xenobiotics
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