Lim Adeline Yl, Segarra Ignacio, Chakravarthi Srikumar, Akram Sufyan, Judson John P
Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
BMC Pharmacol. 2010 Oct 15;10:14. doi: 10.1186/1471-2210-10-14.
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.
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.
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.
舒尼替尼是一种用于治疗胃肠道间质瘤（GIST）和转移性肾细胞癌（mRCC）的酪氨酸激酶抑制剂，它可能与对乙酰氨基酚相互作用，因为二者均经细胞色素P450介导的生物转化以及P-糖蛋白转运。本研究评估了舒尼替尼与对乙酰氨基酚联合给药对肝脏和肾脏功能生物标志物以及肝脏、肾脏、脑、心脏和脾脏组织病理学的影响。将ICR雄性小鼠（每组/每剂量n = 6）给予生理盐水（A组）或腹腔注射500 mg/kg对乙酰氨基酚（B组），或口服25、50、80、100、140 mg/kg舒尼替尼（C组），或口服25、50、80、100、140 mg/kg舒尼替尼并腹腔注射固定剂量500 mg/kg对乙酰氨基酚（D组）。对乙酰氨基酚在舒尼替尼给药前15分钟给予。在舒尼替尼给药后4小时处死小鼠。
A组血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平分别为14.29±2.31 U/L和160.37±24.74 U/L，B组分别升高至249.6±222.7 U/L和377.1±173.6 U/L；C组ALT和AST范围分别为36.75 - 75.02 U/L和204.4 - 290.3 U/L。低剂量舒尼替尼与对乙酰氨基酚联合给药后（D组），ALT和AST浓度分别为182.79 - 221.03 U/L和259.7 - 264.4 U/L，低于B组。高剂量舒尼替尼与对乙酰氨基酚联合给药时ALT和AST值更高（分别为269.6 - 349.2 U/L和430.2 - 540.3 U/L），p < 0.05。肝脏组织病理学显示B组有血管充血；C组有轻度充血（但比B组和D组轻）。在D组中，低剂量舒尼替尼时损伤比B组小，但高剂量舒尼替尼时观察到包括充血在内的更大变化。B组（33.81±5.68 mg/dL）和D组（范围35.01±6.95 U/L至52.85±12.53 U/L）的血尿素氮（BUN）水平高于A组（15.60±2.17 mg/dL）和C组（范围17.50±1.25 U/L至26.68±6.05 U/L），差异有统计学意义（p < 0.05）。肌酐水平保持不变。C组的肾脏充血和坏死低于B组，但D组更高（p > 0.05）。B、C和D组出现轻度心脏毒性。单独给予高剂量舒尼替尼或与对乙酰氨基酚联合给药时均出现脑血管充血。肝脏和肾脏生物标志物与组织病理学征象相关。
对乙酰氨基酚与舒尼替尼联合给药可能导致剂量依赖性结果，表现出轻度肝保护作用或肝毒性增加。高剂量舒尼替尼显示出肾脏、心脏和脑毒性。建议监测肝脏和肾脏功能。
