Biotransformation profiling of [(14)C]ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS).
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.
Cömezoğlu
S Nilgün
SN
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ 08543, USA. s.nilgun.comezoglu@bms.com
Ly
Van T
VT
Zhang
Donglu
D
Humphreys
W Griffith
WG
Bonacorsi
Samuel J
SJ
Everett
Donald W
DW
Cohen
Marvin B
MB
Gan
Jinping
J
Beumer
Jan H
JH
Beijnen
Jos H
JH
Schellens
H M
HM
Lappin
Graham
G
D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D034261:Epothilones / Q000378:metabolism*; D005243:Feces / Q000737:chemistry*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D008657:Metabolic Clearance Rate; D014556:Urine / Q000737:chemistry*
D002250:Carbon Radioisotopes; D034261:Epothilones; C430592:ixabepilone; C093788:epothilone B