1.Histopathological study of the hepatic and renal toxicity associated with the co-administration of Imatinib and Acetaminophen in a preclinical mouse model
Inthisham Nassar ; Thanikachalam Pasupati ; John Paul Judson ; Ignacio Segarra
The Malaysian Journal of Pathology 2010;32(1):1-11
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.
2.Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice.
Moo, Kai Shing ; Radhakrishnan, Shantini ; Teoh, Magdalene ; Narayanan, Prasad ; Bukhari, Nadeem Irfan ; Segarra, Ignacio
Acta Pharmaceutica Sinica 2010;45(7):901-8
Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0-->infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers.
3.Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice.
Kai Shing MOO ; Shantini RADHAKRISHNAN ; Magdalene TEOH ; Prasad NARAYANAN ; Nadeem Irfan BUKHARI ; Ignacio SEGARRA
Acta Pharmaceutica Sinica 2010;45(7):901-908
Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0-->infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers.
Animals
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Antineoplastic Agents
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administration & dosage
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blood
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pharmacokinetics
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Area Under Curve
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Benzamides
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Brain
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metabolism
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Drug Carriers
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administration & dosage
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chemistry
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Half-Life
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Imatinib Mesylate
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Injections, Intravenous
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Liposomes
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administration & dosage
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chemistry
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Male
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Metabolic Clearance Rate
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Mice
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Mice, Inbred ICR
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Piperazines
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administration & dosage
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blood
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pharmacokinetics
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Pyrimidines
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administration & dosage
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blood
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pharmacokinetics
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Tissue Distribution