RT Journal Article
SR Electronic
T1 METABOLISM AND DISPOSITION OF IMATINIB MESYLATE IN HEALTHY VOLUNTEERS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1503
OP 1512
DO 10.1124/dmd.105.004283
VO 33
IS 10
A1 Hans-Peter Gschwind
A1 Ulrike Pfaar
A1 Felix Waldmeier
A1 Markus Zollinger
A1 Claudia Sayer
A1 Peter Zbinden
A1 Michael Hayes
A1 Rolf Pokorny
A1 Michael Seiberling
A1 Monique Ben-Am
A1 Bin Peng
A1 Gerhard Gross
YR 2005
UL http://dmd.aspetjournals.org/content/33/10/1503.abstract
AB Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (tmax 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ± 0.095 μg/ml (mean ± S.D., n = 4) for imatinib and 0.115 ± 0.026 μg/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ± 0.9 h for imatinib, 20.6 ± 1.7 h for CGP74588, and 57.3 ± 12.5 h for 14C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively. The American Society for Pharmacology and Experimental Therapeutics