title: Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug-drug interaction assessment in a mouse model.
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.
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
authors.forename: Jian Ren
authors.initials: JR
authors.lastname: Tan
authors.forename: Srikumar
authors.initials: S
authors.lastname: Chakravarthi
authors.forename: John Paul
authors.initials: JP
authors.lastname: Judson
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Haleagrahara
authors.forename: Ignacio
authors.initials: I
authors.lastname: Segarra
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D001921:Brain / Q000187:drug effects / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D003404:Creatinine / Q000097:blood; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects*; D004347:Drug Interactions; D007211:Indoles / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000473:pathology; D020011:Protective Agents / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D000077210:Sunitinib
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D007211:Indoles; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D004008:Diclofenac; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077210:Sunitinib
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