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.
Highlights
The clinical response to drugs may be affected by the simultaneous administration of other drugs that modify the pharmacokinetics and the disposition profile of medications
The current study aims to assess the effect that coadministration of acetaminophen has on the pharmacokinetics and exposure of imatinib
Mice treated with 100 mg/kg imatinib PO showed a rapid increase in imatinib plasma concentration to reach the Cmax (7.21 ± 0.99 μg/ml) at 2 hours (Tmax)
Summary
The clinical response to drugs may be affected by the simultaneous administration of other drugs that modify the pharmacokinetics and the disposition profile of medications. Drug–drug interaction accounts for about 20-30% of all adverse reactions to drugs and are important in the treatment and management of cancer patients to optimize dosing and manage toxicity associated with the cancer treatment.[1] Imatinib, is a rationally designed potent inhibitor of several protein kinases including BCR-ABL and cKIT. It is approved for the treatment of chronic myeloid leukemia (CML)[2] and gastrointestinal stromal tumors (GIST).[3] Imatinib has been shown to present a variety of drug–drug interactions including antibiotics,[4] immunosuppressant drugs,[5] cardiovascular agents[6] and antifungals[7] among others. The large majority of these interactions involve changes in clearance and bioavailability and have their origin in a common P450 biotransformation pathway which affects the pharmacokinetics and the disposition profile of imatinib such that may require dosing adjustment.[8]
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