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Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice
Adeline Yl Lim1, Ignacio Segarra2, Srikumar Chakravarthi3
1Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Background:
Sunitinib, a tyrosine kinase inhibitor to treat GIST and mRCC may interact with paracetamol as both undergo P450 mediated biotransformation and P-glycoprotein transport. This study evaluates the effects of sunitinib-paracetamol coadministration on liver and renal function biomarkers and liver, kidney, brain, heart and spleen histopathology. ICR male mice (n = 6 per group/dose) were administered saline (group-A) or paracetamol 500 mg/kg IP (group-B), or sunitinib at 25, 50, 80, 100, 140 mg/kg PO (group-C) or coadministered sunitinib at 25, 50, 80, 100, 140 mg/kg PO and paracetamol IP at fixed dose 500 mg/kg (group-D). Paracetamol was administered 15 min before sunitinib. Mice were sacrificed 4 h post sunitinib administration.
Results:
Group-A serum ALT and AST levels were 14.29 ± 2.31 U/L and 160.37 ± 24.74 U/L respectively and increased to 249.6 ± 222.7 U/L and 377.1 ± 173.6 U/L respectively in group-B; group-C ALT and AST ranged 36.75-75.02 U/L and 204.4-290.3 U/L respectively. After paracetamol coadministration with low sunitinib doses (group-D), ALT and AST concentrations ranged 182.79-221.03 U/L and 259.7-264.4 U/L respectively, lower than group-B. Paracetamol coadministration with high sunitinib doses showed higher ALT and AST values (range 269.6-349.2 U/L and 430.2-540.3 U/L respectively), p < 0.05. Hepatic histopathology showed vascular congestion in group-B; mild congestion in group-C (but lesser than in group-B and D). In group-D, at low doses of sunitinib, lesser damage than in group-B occurred but larger changes including congestion were observed at high sunitinib doses. BUN levels were higher (p < 0.05) for group-B (33.81 ± 5.68 mg/dL) and group-D (range 35.01 ± 6.95 U/L to 52.85 ± 12.53 U/L) compared to group-A (15.60 ± 2.17 mg/dL) and group-C (range 17.50 ± 1.25 U/L to 26.68 ± 6.05 U/L). Creatinine remained unchanged. Renal congestion and necrosis was lower in group-C than group-B but was higher in group-D (p > 0.05). Mild cardiotoxicity occurred in groups B, C and D. Brain vascular congestion occurred at high doses of sunitinib administered alone or with paracetamol. Hepatic and renal biomarkers correlated with histopathology signs.
Conclusions:
Paracetamol and sunitinib coadministration may lead to dose dependent outcomes exhibiting mild hepatoprotective effect or increased hepatotoxicity. Sunitinib at high doses show renal, cardiac and brain toxicity. Liver and renal function monitoring is recommended.
Insights
This study shows that combining sunitinib and paracetamol can have dose-dependent effects on liver and kidney function in mice. High doses of sunitinib alone or with paracetamol may cause organ toxicity, necessitating careful monitoring.
Area of Science:
- Pharmacology and Toxicology
- Drug Interactions
- Biomarker Analysis
Background:
- Sunitinib, a tyrosine kinase inhibitor, and paracetamol undergo similar metabolic pathways.
- Potential for drug-drug interactions exists between sunitinib and paracetamol.
- This study investigates their combined effects on organ function and pathology.
Purpose of the Study:
- To evaluate the impact of sunitinib-paracetamol coadministration on liver and renal biomarkers.
- To assess the histopathological changes in various organs (liver, kidney, brain, heart, spleen) following coadministration.
- To determine dose-dependent effects and potential toxicities.
Main Methods:
- ICR male mice were used, divided into groups receiving saline, paracetamol, sunitinib alone, or sunitinib-paracetamol combination.
- Doses of sunitinib ranged from 25 to 140 mg/kg, with paracetamol administered at 500 mg/kg.
- Organ function biomarkers (ALT, AST, BUN, creatinine) and histopathology were analyzed 4 hours post-administration.
Main Results:
- Paracetamol coadministration with low-dose sunitinib showed lower ALT/AST than paracetamol alone.
- High-dose sunitinib with paracetamol significantly increased ALT/AST levels, indicating hepatotoxicity.
- Sunitinib at high doses induced renal, cardiac, and brain toxicity, with vascular congestion observed in the brain.
Conclusions:
- Sunitinib-paracetamol coadministration exhibits dose-dependent effects, ranging from mild hepatoprotection to increased hepatotoxicity.
- High-dose sunitinib poses risks of renal, cardiac, and brain toxicity.
- Monitoring of liver and renal function is crucial when these drugs are coadministered.
