Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice.
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.
Lim
Adeline Yl
AY
Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Segarra
Ignacio
I
Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Chakravarthi
Srikumar
S
Department of Pathology, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Akram
Sufyan
S
Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Judson
John P
JP
Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D058633:Antipyretics / Q000633:toxicity; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006940:Hyperemia / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009336:Necrosis / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D011758:Pyrroles / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D000077210:Sunitinib
D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D058633:Antipyretics; D015415:Biomarkers; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000082:Acetaminophen; D000077210:Sunitinib