Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
Naunyn Schmiedebergs Arch Pharmacol. 2013 Jul;386(7):619-33. doi: 10.1007/s00210-013-0861-4. Epub 2013 Apr 5.
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.
舒尼替尼是一种用于 GIST 和晚期肾细胞癌的酪氨酸激酶抑制剂。双氯芬酸用于癌症疼痛管理。联合用药可能会介导 P450 毒性。我们评估了它们的相互作用，评估了生物标志物 ALT、AST、BUN、肌酐以及肝、肾、心、脑和脾的组织病理学变化。我们给 ICR 小鼠（雄性，每组/剂量 6 只）注射生理盐水（A 组）或 30mg/kg 双氯芬酸 ip（B 组），或口服 25、50、80、100、140mg/kg 舒尼替尼（C 组）或联合使用 30mg/kg 双氯芬酸（ip）和 25、50、80、100、140mg/kg 舒尼替尼（po）。双氯芬酸在舒尼替尼给药前 15 分钟给药，在舒尼替尼给药后 4 小时处死小鼠，评估生物标志物和组织病理学。A 组 AST 为 92.2 ± 8.0 U/L，B 组为 159.7 ± 14.6 U/L（p < 0.05）；C 组 AST 范围为 105.1-152.6 U/L，D 组为 156.0-209.5 U/L（p < 0.05）。A 组 ALT 为 48.9 ± 1.6 U/L，B 组为 95.1 ± 4.5 U/L（p < 0.05），C 组为 50.5-77.5 U/L，D 组为 82.3-115.6 U/L（p < 0.05）。肾功能生物标志物 BUN 为 16.3 ± 0.6mg/dl（A 组），在 B 组增加至 29.9 ± 2.6mg/dl（p < 0.05），范围为 19.1-33.3mg/dl（p < 0.05）和 26.9-40.8mg/dl 在 C 和 D 组，分别。A 组肌酐为 5.9pmol/ml；B 组为 6.2pmol/ml（p < 0.01），C 组和 D 组范围分别为 6.0-6.2 和 6.2-6.4pmol/ml（p < 0.05 为 D）。组织病理学评估（血管和炎症损伤）显示 B 组有毒性（p < 0.05），C 组有轻度毒性。D 组的损伤明显小于 B 组（p < 0.05）。脾仅在联合用药后出现毒性。这些结果表明舒尼替尼具有血管和炎症保护作用，但生物标志物分析未显示。
