Metabolism and disposition of imatinib mesylate in healthy volunteers.
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 (14)C-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 (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/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 (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 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.
Gschwind
Hans-Peter
HP
Exploratory Development/DMPK, Novartis Pharma AG, WKL-135.2.25, CH-4002 Basel, Switzerland. hans-peter.gschwind@novartis.com
Pfaar
Ulrike
U
Waldmeier
Felix
F
Zollinger
Markus
M
Sayer
Claudia
C
Zbinden
Peter
P
Hayes
Michael
M
Pokorny
Rolf
R
Seiberling
Michael
M
Ben-Am
Monique
M
Peng
Bin
B
Gross
Gerhard
G
D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001549:Benzamides; D001711:Biotransformation; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005243:Feces / Q000737:chemistry; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019389:Cytochrome P-450 CYP2D6