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- Title
Histopathological study of the hepatic and renal toxicity associated with the co-administration of Imatinib and Acetaminophen in a preclinical mouse model.
- Authors
Bmedsci, Inthisham Nassar; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio
- Abstract
Imatinib, a selective tyrosine kinase inhibitor, is the fi rst line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrifi ced at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n=4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.
- Subjects
IMATINIB; INSULIN synthesis inhibitors; CHRONIC myeloid leukemia; NEPHROTOXICOLOGY; HEPATOTOXICOLOGY; ACETAMINOPHEN; CANCER pain
- Publication
Malaysian Journal of Pathology, 2010, Vol 32, Issue 1, p1
- ISSN
0126-8635
- Publication type
Article