Metabolism and Disposition of Imatinib Mesylate in Healthy Volunteers

Abstract

ABSTRACT: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 g/ml (mean ؎ S.D., n ‫؍‬ 4) for imatinib and 0.115 ؎ 0.026 g/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.

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…IM is predominantly excreted through the biliary-fecal route 41 and BCRP is highly expressed in the small intestine and bile canaliculi of the liver. 42,43 The presence of BCRP in the small intestine suggests that it contributes to the regulation of substrate uptake from the gastrointestinal tract through back-transport of substrates reentering the gut lumen.…”

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

“…Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML show that orally administered imatinib is well absorbed and has an absolute bioavailability of 98% irrespective of the oral dosage form (solution, capsule, tablet) or dosage strength (100 mg, 400 mg) [1,2]. The terminal elimination half-life of imatinib is approximately 18 hours [2] and the main elimination pathway is via the biliary-fecal route [3].…”