Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry.
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 [14C]-levels (100 microCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-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 [14C]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.
Beumer
J H
JH
Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. BEUMERJH@UPMC.EDU
Garner
R C
RC
Cohen
M B
MB
Galbraith
S
S
Duncan
G F
GF
Griffin
T
T
Beijnen
J H
JH
Schellens
J H M
JH
D000230:Adenocarcinoma / Q000378:metabolism; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D003110:Colonic Neoplasms / Q000378:metabolism; D034261:Epothilones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D012811:Sigmoid Neoplasms / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods
D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone