Histopathological study of the hepatic and renal toxicity associated with the co-administration of Imatinib and Acetaminophen in a preclinical mouse model
- Author:
Inthisham Nassar
;
Thanikachalam Pasupati
;
John Paul Judson
;
Ignacio Segarra
- Publication Type:Journal Article
- Keywords:
Imatinib, acetaminophen, histopathology, drug-drug interaction, hepatotoxicity, renal toxicity
- From:The Malaysian Journal of Pathology
2010;32(1):1-11
- CountryMalaysia
- Language:English
-
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.
- Full text:W020151209345283440264.pdf
