Received for publication March 21, 2005.
Revised July 1, 2005.
Accepted for publication July 6, 2005.

METABOLISM AND DISPOSITION OF IMATINIB MESYLATE IN HEALTHY VOLUNTEERS

Abstract

Imatinib mesylate (GLEEVEC^®, GLIVEC^®, formerly STI571) has demonstrated unprecedented efficacy as first line therapy for treatment for all phases of chronic myelogenous leukemia (CML) and metastatic and unresectable malignant gastrointestinal stromal tumors (GIST). Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg ¹⁴C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib and its main metabolite CGP74588. Metabolite patterns were determined by radio-HPLC with off-line micro-plate solid scintillation counting and characterized by LC-MS. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t_max 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. About 65% and 9% of total systemic exposure (AUC_0-24h of radioactivity) corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and of 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.

Key words: anticancer agents, clinical pharmacokinetics, drug absorption, drug disposition, excretion, hepatobiliary disposition, human pharmacokinetics, mass spectrometry, metabolite identification, metabolite kinetics

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