Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

被引:34
作者
Beumer, J. H.
Garner, R. C.
Cohen, M. B.
Galbraith, S.
Duncan, G. F.
Griffin, T.
Beijnen, J. H.
Schellens, J. H. M.
机构
[1] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA
[2] Netherlands Canc Inst, Slotervaart Hosp, Dept Pharm & Pharmacol, Amsterdam, Netherlands
[3] Xceleron, York, N Yorkshire, England
[4] Bristol Myers Squibb Clin Discovery, Princeton, NJ USA
[5] Univ Utrecht, Fac Pharmaceut Sci, Dept Biomed Anal, Div Drug Toxicol, NL-3508 TC Utrecht, Netherlands
[6] Netherlands Canc Inst, Antoni Leeuwenhoek Hosp, Dept Med Oncol, Amsterdam, Netherlands
关键词
Ixabepilone; Epothilone; Mass balance; Accelerator mass spectrometry; Anti-cancer agent;
D O I
10.1007/s10637-007-9041-z
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [C-14]-levels (100 mu Ci in a typical human radio-tracer study). This necessitated the use of much lower levels of [C-14]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [C-14]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.
引用
收藏
页码:327 / 334
页数:8
相关论文
共 32 条
[1]   Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days [J].
Abraham, J ;
Agrawal, M ;
Bakke, S ;
Rutt, A ;
Edgerly, M ;
Balis, FM ;
Widemann, B ;
Davis, L ;
Damle, B ;
Sonnichsen, D ;
Lebwohl, D ;
Bates, S ;
Kotz, H ;
Fojo, T .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (09) :1866-1873
[2]  
AGHAJANIAN C, 2007, J CLIN ONCOL 0129
[3]   Epothilones: A novel class of non-taxane microtubule-stabilizing agents [J].
Altaha, R ;
Fojo, T ;
Reed, E ;
Abraham, J .
CURRENT PHARMACEUTICAL DESIGN, 2002, 8 (19) :1707-1712
[4]  
Bayés M, 2004, METHOD FIND EXP CLIN, V26, P53
[5]   Mass balance studies, with a focus an anticancer drugs [J].
Beumer, JH ;
Beijnen, JH ;
Schellens, JHM .
CLINICAL PHARMACOKINETICS, 2006, 45 (01) :33-58
[6]  
BOLLAG DM, 1995, CANCER RES, V55, P2325
[7]   A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products [J].
Borzilleri, RM ;
Zheng, XP ;
Schmidt, RJ ;
Johnson, JA ;
Kim, SH ;
DiMarco, JD ;
Fairchild, CR ;
Gougoutas, JZ ;
Lee, FYF ;
Long, BH ;
Vite, GD .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (37) :8890-8897
[8]   Clinical and preclinical pharmacokinetics of raltitrexed [J].
Clarke, SJ ;
Beale, PJ ;
Rivory, LP .
CLINICAL PHARMACOKINETICS, 2000, 39 (06) :429-443
[9]  
Felip E, 2002, TUMORI, pS17
[10]   A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts [J].
Garner, RC ;
Barker, J ;
Flavell, C ;
Garner, JV ;
Whattam, M ;
Young, GC ;
Cussans, N ;
Jezequel, S ;
Leong, D .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2000, 24 (02) :197-209