Biotransformation Profiling of [¹⁴C]Ixabepilone in Human Plasma, Urine and Feces Samples Using Accelerator Mass Spectrometry (AMS)

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.