Reduced exposure of imatinib after coadministration with acetaminophen in mice.
OBJECTIVE
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.


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 AUC(0-12) was 27.04 +/- 0.38 mg.h/ml, C(max) was 7.21 +/- 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC(0-12) and C(max) 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.
Departments of Pathology, International Medical University; No. 126, Jalan 19/155B, Bukit Jalil-57000 Kuala Lumpur, Malaysia.
Inthisham
I
Nassar
Thanikachalam
T
Pasupati
John Paul
JP
Judson
Ignacio
I
Segarra