Pharmacokinetics, tissue distribution and bioavailability of imatinib in mice after administration of a single oral and an intravenous bolus dose

Imatinib inhibits Bcr-Abl, c-KIT and PDGFR kinases involved in chronic myelogenous leukemia and gastrointestinal stromal tumors. Mice were given imatinib PO (50 mg/kg) or IV (12.5 mg/kg) and plasma, liver, brain, spleen, kidney disposition profiles analyzed. Plasma t1/2 was 4.5 h. IV plasma AUC0→∞ was 11.59 μg·h/mL, MRT was 4.87 h, Cl was 1.08 l/h/kg and VSS was 5.23 l/kg. PO AUC0→∞ was 12.82 μg·h/mL, MRT 5.1 h, CMAX was 6.99 ± 2.84 μg/mL, absorption rate constant, Ka was 4.348 h–1, bioavailability was 27.7%, VSS was 5.51 l/kg. The hepatic extraction ratio was 0.384 and the minimum dose fraction absorbed was 0.450. IV AUC0→∞ tissue-to-plasma ratios were 2.59 (spleen, kidney) and 2.91 (liver) but increased after PO administration in spleen (3.68) and kidney (3.49) and decreased in liver (2.75). Liver and kidney correlations with plasma concentrations suggests perfusion-limited uptake. Spleen counter-clockwise profile suggests non-concentration dependent uptake. Brain penetration was minimal.