Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug-drug interaction assessment in a mouse model

Tan, Jian Ren, Chakravarthi, Srikumar, Judson, John Paul, Haleagrahara, Nagaraja, and Segarra, Ignacio (2013) Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug-drug interaction assessment in a mouse model. Naunyn-Schmiedebergs Archives of Pharmacology, 386 (7). pp. 619-633.

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Abstract

Sunitinib is a tyrosine kinase inhibitor for GIST and advanced renal cell carcinoma. Diclofenac is used in cancer pain management. Coadministration may mediate P450 toxicity. We evaluate their interaction, assessing biomarkers ALT, AST, BUN, creatinine, and histopathological changes in the liver, kidney, heart, brain, and spleen. ICR mice (male, n = 6 per group/dose) were administered saline (group A) or 30 mg/kg diclofenac ip (group B), or sunitinib po at 25, 50, 80, 100, 140 mg/kg (group C) or combination of diclofenac (30 mg/kg, ip) and sunitinib (25, 50, 80, 100, 140 mg/kg po). Diclofenac was administered 15 min before sunitinib, mice were euthanized 4 h post-sunitinib dose, and biomarkers and tissue histopathology were assessed. AST was 92.2 ± 8.0 U/L in group A and 159.7 ± 14.6 U/L in group B (p < 0.05); in group C, it the range was 105.1-152.6 U/L, and in group D, it was 156.0-209.5 U/L (p < 0.05). ALT was 48.9 ± 1.6 U/L (group A), 95.1 ± 4.5 U/L (p < 0.05) in group B, and 50.5-77.5 U/L in group C and 82.3-115.6 U/L after coadministration (p < 0.05). Renal function biomarker BUN was 16.3 ± 0.6 mg/dl (group A) and increased to 29.9 ± 2.6 mg/dl in group B (p < 0.05) and it the range was 19.1-33.3 mg/dl (p < 0.05) and 26.9-40.8 mg/dl in groups C and D, respectively. Creatinine was 5.9 pmol/ml in group A; 6.2 pmol/ml in group B (p < 0.01), and the range was 6.0-6.2 and 6.2-6.4 pmol/ml in groups C and D, respectively (p < 0.05 for D). Histopathological assessment (vascular and inflammation damages) showed toxicity in group B (p < 0.05) and mild toxicity in group C. Damage was significantly lesser in group D than group B (p < 0.05). Spleen only showed toxicity after coadministration. These results suggest vascular and inflammation protective effects of sunitinib, not shown after biomarker analysis.

Item ID: 30392
Item Type: Article (Research - C1)
ISSN: 1432-1912
Keywords: sunitinib, diclofenac, hepatoprotective effect, histopathology, biomarker
Funders: International Medical University
Projects and Grants: International Medical University grant BMS I01-2010(05)
Date Deposited: 27 Nov 2013 09:26
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111502 Clinical Pharmacology and Therapeutics @ 75%
11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 80%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920105 Digestive System Disorders @ 20%
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