Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice

Abstract

BackgroundSunitinib, 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.ResultsGroup-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.ConclusionsParacetamol 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.

Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study

“…Treatment of mice with NAC at 1.5 h post-APAP injection significantly reversed the biochemical changes and reduced necrosis and TUNEL-positivity (Saito et al, 2010). A significant correlation was found between ALT and aspartate aminotransferase (AST) levels and the hepatic vascular congestion and inflammatory changes 4 hours post-APAP administration (Lim et al, 2010). APAP overdose in mice significantly increased serum AST level which was reduced using NAC to about 20% of its level.…”

“…A significant correlation was found between plasma urea, but not creatinine, level and the APAP-induced renal vascular and inflammatory changes 4 hours post-APAP administration. This indicates that creatinine is not an early indicator of APAP renal toxicity or that 4 hours time point is too early to detect a significant rise in the creatinine level (Lim et al, 2010).…”

Oral thearubigins do not protect against acetaminopheninduced hepatotoxicity in mice

“…It is well established that acetaminophen (APAP) overdose in mice causes hepatotoxicity manifested by increases in serum ALT level, hepatic CYP2E1 level, and serum and hepatic MDA levels in addition to decreases in serum and hepatic GSH levels [1,18]. Morphologically, the liver sections showed cellular necrosis, vacuolization, and degeneration around the centrilobular veins.…”

Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors

“…All drugs were purchased from the LC Laboratories (Woburn, MA, USA; CAS numbers: motesanib: 453562-69-1, pazopanib: 444731-52-6, sorafenib: 284461-73-0, sunitinib: 557795-19-4, vatalanib: 212141-54-3) at >99% purity and were suspended in 2% carboxymethylcellulose with 2 mg/mL methyl-4-hydroxibenzoate (both from Sigma Aldrich) before treatments. The administration and treatment dose for each compound were established to be tolerable and effective according to the literature 15, 20-35. Control mice received only the suspending medium.…”