Reduced exposure of imatinib after coadministration with acetaminophen in mice

Abstract

Purpose:Imatinib is an efficacious drug against chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) due to selective inhibition of c-KIT and BCR-ABL kinases. It presents almost complete bioavailability, is eliminated via P450-mediated metabolism and is well tolerated. However, a few severe drug-drug interactions have been reported in cancer patients taking acetaminophen.Materials and Methods:Male ICR mice were given 100 mg/kg single dose of imatinib orally or imatinib 100 mg/kg (orally) coadministered with acetaminophen intraperitoneally (700 mg/kg). Mice were euthanized at predetermined time points, blood samples collected, and imatinib plasma concentration measured by HPLC.Results:Imatinib AUC0-12 was 27.04 ± 0.38 mg·h/ml, Cmax was 7.21 ± 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC0-12 and Cmax decreased 56% and 59%, respectively and a longer half-life was observed (5.6 hours).Conclusions:The study shows a pharmacokinetic interaction between acetaminophen and imatinib which may render further human studies necessary if both drugs are administered concurrently to cancer patients.

The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide

“…Taking the above-mentioned facts into consideration, this study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect, as previously suggested (Weise et al 2009 ; Lim et al 2010 ). However, we have to remember that in the present study, the administered doses of paracetamol and sunitinib were relatively low in comparison to doses in the previously mentioned publications (sunitinib 25–140 mg/kg and paracetamol 500 mg/kg (Lim et al 2010 ; Kim et al 2009b ), paracetamol 700 mg/kg (Nassar et al 2009 , 2010 ) and 1,000 mg/kg (Kim et al 2011 ); the route of paracetamol administration was also different (Lim et al 2010 ; Nassar et al 2009 , 2010 ; Kim et al 2011 ). In higher doses, these drugs may be hepatotoxic (Weise et al 2009 ; Yapar et al 2007 ).…”

“…Sunitinib lowers maximum plasma concentrations of paracetamol glucuronide. Referring to the obtained pharmacokinetics of paracetamol, it is possible that overall bioavailability of acetaminophen is decreased in the presence of sunitinib, contrary to results of Nassar et al ( 2009 , 2010 ), suggesting different mechanisms of metabolism of acetaminophen coadministered with sunitinib than with imatinib.…”

“…Fasting before administration of acetaminophen (Weise et al 2009 ; Lim et al 2010 ; Nassar et al 2009 , 2010 ) could enhance the effects of low doses of acetaminophen in the present study by reducing hepatic glutathione levels (Jaeschke et al 2011 ; Fernando and Ariyananda 2009 ).…”

“…However, when assessing the t max of sunitinib in the presence of paracetamol, we have noticed that paracetamol decreases the time necessary for sunitinib to reach maximum plasma concentration, but does not affect its elimination. There was no effect of acetaminophen on the pharmacokinetics of SU12662, which suggests that paracetamol does not alter the cytochrome P450 pathway of sunitinib, but may enhance bioavailability by increasing the free fraction of sunitinib, as suggested with coadministration of imatinib and acetaminophen (Nassar et al 2009 ).…”

Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma

“…The plasma C max of imatinib in male ICR mice was determined to be 17 μM 2 h after administration of 100 mg/kg p.o. [ 38 ]. The plasma half-life of imatinib in mice was determined to be 2.3 h [ 38 ], whereas in humans it is around 10 h [ 39 ].…”