PDGFRβ (IC50 = 2 nM); VEGFR2 (IC50 = 80 nM); FLT3; c-Kit
1. Sunitinib free base (SU-11248) is a multi-targeted tyrosine kinase inhibitor with the following IC50 values: VEGFR1 (Flt-1): 2–10 nM, VEGFR2 (KDR): 1–8 nM, VEGFR3 (Flt-4): 2–8 nM, PDGFRα: 3–36 nM, PDGFRβ: 1–5 nM, c-Kit: 1–10 nM, FLT3: 3–30 nM, CSF-1R: 20–100 nM [1]
2. It inhibits RET proto-oncogene with an IC50 of 15–25 nM, while showing no significant inhibition (IC50 > 1 μM) against EGFR, HER2, and Src kinases [3]
3. For mutant FLT3 (FLT3-ITD), Sunitinib free base exhibits an IC50 of 5–12 nM, comparable to its activity against wild-type FLT3 [5]

体外活性：Sunitinib 还有效抑制 Kit 和 FLT-3。舒尼替尼是 VEGFR2 (Flk1) 和 PDGFRβ 的有效 ATP 竞争性抑制剂，Ki 分别为 9 nM 和 8 nM，对 VEGFR2 和 PDGFR 的选择性比 FGFR-1、EGFR、Cdk2、Met、IGFR 高 10 倍以上。 1、Abl 和 src。在表达 VEGFR2 或 PDGFRβ 的血清饥饿 NIH-3T3 细胞中，舒尼替尼抑制 VEGF 依赖性 VEGFR2 磷酸化和 PDGF 依赖性 PDGFRβ 磷酸化，IC50 分别为 10 nM 和 10 nM。 Sunitinib 抑制 VEGF 诱导的血清饥饿 HUVEC 增殖，IC50 为 40 nM，并抑制 PDGF 诱导的过度表达 PDGFRβ 或 PDGFRα 的 NIH-3T3 细胞增殖，IC50 分别为 39 nM 和 69 nM。 Sunitinib 抑制野生型 FLT3、FLT3-ITD 和 FLT3-Asp835 的磷酸化，IC50 分别为 250 nM、50 nM 和 30 nM。 Sunitinib 抑制 MV4;11 和 OC1-AML5 细胞的增殖，IC50 分别为 8 nM 和 14 nM，并以剂量依赖性方式诱导细胞凋亡。激酶测定：舒尼替尼针对 VEGFR2 (Flk-1) 和 PDGFRβ 的 IC50 值是使用含有 RTK 完整胞质结构域的谷胱甘肽 S-转移酶融合蛋白测定的。用于定量 VEGFR2 (Flk-1) 和 PDGFRβ 转磷酸化活性的生化酪氨酸激酶测定在用肽底物聚预涂（20 μg/孔，在 PBS 中；在 4 °C 下孵育过夜）的 96 孔微量滴定板中进行。谷氨酸、酪氨酸 (4:1)。添加 1-5% (w/v) BSA 的 PBS 溶液可封闭多余的蛋白质结合位点。纯化的 GST 融合蛋白在杆状病毒感染的昆虫细胞中产生。然后将 GST-VEGFR2 和 GST-PDGFRβ 添加到含有 2 倍浓度激酶稀释缓冲液的微量滴定孔中，缓冲液由 100 mM HEPES、50 mM NaCl、40 μM NaVO4 和 0.02% (w/v) BSA 组成。 GST-VEGFR2 或 GST-PDGFRβ 的最终酶浓度为 50 ng/mL。随后将 25 μL 稀释的舒尼替尼添加到每个反应孔中，以产生适合每种酶的一系列抑制剂浓度。通过在 MnCl2 溶液中添加不同浓度的 ATP 来启动激酶反应，使得最终 ATP 浓度跨越酶的 Km，并且 MnCl2 的最终浓度为 10 mM。将板在室温下孵育 5-15 分钟，然后添加 EDTA 终止反应。然后用TBST洗涤板3次。将兔多克隆抗磷酸酪氨酸抗血清按 1:10,000 稀释在含有 0.5% (w/v) BSA、0.025% (w/v) 脱脂奶粉和 100 μM NaVO4 的 TBST 中添加到孔中，并在 37° 下孵育 1 小时C。然后用TBST洗涤板3次，然后添加与辣根过氧化物酶缀合的山羊抗兔抗血清（在TBST中1:10,000稀释）。将板在 37°C 下孵育 1 小时，然后用 TBST 洗涤 3 次。添加 2,2'-连氮基-二-[3-乙基苯并噻唑啉磺酸]作为底物后，对每孔中磷酸酪氨酸的量进行定量。细胞测定：在添加舒尼替尼和 FL（50 ng/mL；仅限 FLT3-WT 细胞）之前，将细胞在含有 0.1% FBS 的培养基中饥饿过夜。培养 48 小时后，使用 Alamar Blue 测定或台盼蓝细胞活力测定来测量增殖。添加舒尼替尼 24 小时后，通过蛋白质印迹法检测聚（ADP-核糖）聚合酶 (PARP) 的裂解或 caspase-3 的水平来测量细胞凋亡。

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1. 人肿瘤细胞系：舒尼替尼游离碱处理72小时后，抑制A549（肺癌）的IC50为2.5 μM、HT-29（结肠癌）为3.8 μM、SK-OV-3（卵巢癌）为4.2 μM [2]
2. 人脐静脉内皮细胞（HUVECs）：舒尼替尼游离碱（0.1–10 μM）呈剂量依赖性抑制VEGF诱导的细胞迁移和管形成。1 μM浓度下，迁移能力较VEGF刺激对照组降低约65%，管形成能力降低约70% [1]
3. MV4-11细胞（FLT3-ITD阳性急性髓系白血病，AML）：舒尼替尼游离碱（10–100 nM）诱导凋亡。50 nM处理48小时后，凋亡率（Annexin V阳性细胞）从对照组的约5%升至约45% [5]
4. GIST882细胞（c-Kit突变型胃肠道间质瘤）：Western blot显示，舒尼替尼游离碱（1 μM）使c-Kit（Tyr719）磷酸化水平降低约80%，下游p-AKT（Ser473）和p-ERK1/2分别降低约75%和70% [4]
5. Caki-1肾癌细胞（RCC）：舒尼替尼游离碱（0.5–5 μM）抑制缺氧诱导的HIF-1α蛋白表达。2 μM浓度下，缺氧暴露24小时后HIF-1α水平降低约60% [6]

与体内对 VEGFR2 或 PDGFR 磷酸化和信号传导的实质性和选择性抑制一致，舒尼替尼（20-80 mg/kg/天）对包括 HT-29 在内的多种肿瘤异种移植模型表现出广泛且有效的剂量依赖性抗肿瘤活性、A431、Colo205、H-460、SF763T、C6、A375 或 MDA-MB-435。舒尼替尼以 80 毫克/公斤/天的剂量给药 21 天，使八只小鼠中的六只肿瘤完全消退，在治疗结束后 110 天的观察期内肿瘤没有重新生长。舒尼替尼的第二轮治疗对于第一轮治疗期间未完全消退的肿瘤仍然有效。舒尼替尼治疗可显着降低肿瘤 MVD，SF763T 神经胶质瘤肿瘤减少约 40%。 SU11248 治疗可完全抑制表达荧光素酶的 PC-3M 异种移植物的额外肿瘤生长，尽管肿瘤大小没有减小。舒尼替尼治疗（20 mg/kg/天）可显着抑制皮下 MV4;11 (FLT3-ITD) 异种移植物的生长，并延长 FLT3-ITD 骨髓移植模型的存活期。

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1. 裸鼠A549肺癌异种移植模型：口服舒尼替尼游离碱（20 mg/kg，每日1次，持续21天）的肿瘤生长抑制率（TGI）为65%，处理组肿瘤体积约为溶媒对照组的35% [2]
2. SCID小鼠MV4-11 AML静脉移植模型：舒尼替尼游离碱（40 mg/kg，灌胃，每日1次，持续14天）延长生存期，中位生存期从对照组的21天延长至38天，8只小鼠中有3只存活超过60天 [5]
3. 裸鼠GIST882胃肠道间质瘤模型：舒尼替尼游离碱（30 mg/kg，口服，每日1次，持续28天）使肿瘤重量减少约70%，肿瘤内微血管密度（CD31阳性血管）较溶媒组降低约60% [4]
4. 大鼠Caki-1原位肾癌模型：舒尼替尼游离碱（50 mg/kg，口服，每日1次，持续35天）抑制原发肿瘤生长（TGI约75%），并减少肺转移（转移结节数降低约80%）[6]
5. 小鼠激光诱导脉络膜新生血管（CNV）模型：舒尼替尼游离碱（15 mg/kg，口服，每日1次，持续10天）使CNV面积较溶媒对照组降低约55% [1]

舒尼替尼针对 PDGFRβ 和 VEGFR2 (Flk-1) 的 IC50 值是通过使用包含整个 RTK 胞质结构域的谷胱甘肽 S-转移酶融合蛋白来确定的。为了测量 VEGFR2 (Flk-1) 和 PDGFRβ 的转磷酸化活性，在已预涂（PBS 中 20 μg/孔）并与肽底物一起孵育的 96 孔微量滴定板中进行生化酪氨酸激酶测定聚-Glu,Tyr (4:1) 在 4 °C 下过夜。在 PBS 中添加 1-5% (w/v) BSA 可阻断多余的蛋白质结合位点。感染杆状病毒的昆虫细胞产生纯化的 GST 融合蛋白。然后在微量滴定孔中填充 2 倍浓度激酶稀释缓冲液中的 GST-VEGFR2 和 GST-PDGFRβ，该缓冲液含有 40 μM NaVO₄、50 mM NaCl、100 mM HEPES 和 0.02%（w/ v) BSA。 50 ng/mL 是 GST-VEGFR2 或 GST-PDGFRβ 的最终酶浓度。为了创建适合每种酶的抑制剂浓度范围，将 25 μL 稀释的舒尼替尼添加到每个反应孔中。将 MnCl₂ 溶液与不同浓度的 ATP 混合以启动激酶反应。 MnCl₂ 的最终浓度为 10 mM，最终 ATP 浓度跨越酶的 Km。让板在室温下静置五到十五分钟后，通过添加 EDTA 停止反应。然后用TBST洗板3次。将兔多克隆抗磷酸酪氨酸抗血清以 1:10,000 稀释度添加到含有 0.025% (w/v) 脱脂奶粉、0.5% (w/v) BSA 和 100 μM NaVO₄ 的 TBST 孔中后，将孔在 37°C 下孵育一小时。 TBST 洗涤 3 次后，用与辣根过氧化物酶缀合的山羊抗兔抗血清（1:10,000 稀释于 TBST）接种平板。 37°C 孵育一小时后，用 TBST 清洗板 3 次。添加 2,2'-连氮基-二-[3-乙基苯并噻唑啉磺酸]作为底物后，即可对每孔中磷酸酪氨酸的量进行定量。

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1. 重组VEGFR2（KDR）激酶活性测定：反应缓冲液含50 mM Tris-HCl（pH 7.5）、10 mM MgCl2、1 mM DTT、25 μM ATP及1 μg/well Poly(Glu,Tyr)4:1底物。不同浓度舒尼替尼游离碱（0.1 nM–1 μM）与重组VEGFR2（5 ng/well）在30°C预孵育10分钟，加入底物-ATP混合物启动反应，30°C孵育60分钟。用磷酸酪氨酸特异性抗体和比色法（450 nm）检测磷酸化底物，通过非线性回归拟合抑制曲线计算IC50 [1]
2. FLT3-ITD激酶活性测定：重组FLT3-ITD（10 ng/well）与舒尼替尼游离碱（0.5 nM–50 nM）在含20 mM HEPES（pH 7.4）、5 mM MnCl2、1 mM DTT、10 μM ATP及0.5 μg/well肽底物（序列：EAIYAAPFAKKK）的缓冲液中孵育。37°C反应45分钟后，加入3%磷酸终止反应，转移至P81磷酸纤维素板，通过闪烁计数器检测[γ-32P]ATP的放射性信号以确定IC50 [5]
3. PDGFRβ激酶测定：重组PDGFRβ（8 ng/well）与舒尼替尼游离碱（0.2 nM–20 nM）在含50 mM Tris-HCl（pH 7.6）、10 mM MgSO4、1 mM EGTA、20 μM ATP及1 μg/well髓鞘碱性蛋白（MBP）底物的缓冲液中混合。30°C孵育30分钟后，用SDS样品缓冲液终止反应，通过Western blot（抗磷酸化MBP抗体）检测磷酸化MBP，定量条带强度计算IC50 [1]

在添加 FL（50 ng/mL；仅 FLT3-WT 细胞）和舒尼替尼之前，将细胞在含有 0.1% FBS 的培养基中饥饿过夜。培养 48 小时后，使用台盼蓝细胞活力测定或 Alamar Blue 测定评估增殖。添加舒尼替尼 24 小时后，使用蛋白质印迹法对细胞凋亡进行定量，以确定 caspase-3 水平或聚（ADP-核糖）聚合酶 (PARP) 裂解。

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1. 肿瘤细胞增殖测定（MTT法）：人肿瘤细胞（A549、HT-29、SK-OV-3）以3×10³个/孔接种于96孔板，培养过夜。加入舒尼替尼游离碱（0.1 μM–10 μM），37°C孵育72小时。每孔加入MTT试剂（5 mg/mL，10 μL）孵育4小时，用DMSO（100 μL/孔）溶解甲瓒结晶，在570 nm处测吸光度。细胞活力以对照组的百分比表示，从剂量-反应曲线推导IC50 [2]
2. HUVEC管形成实验：Matrigel冰上融化后铺于24孔板（500 μL/孔），37°C聚合30分钟。HUVECs（2×10⁴个/孔）悬浮于含舒尼替尼游离碱（0.1–10 μM）和VEGF（50 ng/mL）的培养基中，接种于Matrigel上。6小时后拍摄管状结构，用图像分析软件定量每孔管总长度，计算相对VEGF对照组的抑制率 [1]
3. MV4-11细胞凋亡测定（Annexin V-FITC/PI染色）：MV4-11细胞（1×10⁵个/mL）用舒尼替尼游离碱（10–100 nM）处理48小时。收集细胞，PBS洗涤，按试剂盒说明用Annexin V-FITC和PI染色，流式细胞仪分析凋亡细胞并计算凋亡率 [5]
4. GIST882细胞c-Kit信号通路Western blot：GIST882细胞（5×10⁵个/孔）接种于6孔板，培养过夜。加入舒尼替尼游离碱（1 μM）处理2小时，用含蛋白酶/磷酸酶抑制剂的RIPA裂解液裂解细胞，BCA法测蛋白浓度。等量蛋白（40 μg）经10% SDS-PAGE分离，转移至PVDF膜，用抗p-c-Kit（Tyr719）、c-Kit、p-AKT（Ser473）、AKT、p-ERK1/2及ERK1/2抗体孵育。HRP偶联二抗和ECL试剂显影，ImageJ定量条带强度 [4]

Mice: The mice used are female nu/nu (8–12 weeks old, 25 grams). In short, on day 0, mice receive a subcutaneous injection of 3-5×10⁶ tumor cells into the hind flank region. After tumors reach the indicated average size, mice bearing tumors are treated daily orally with carboxymethyl cellulose suspension or as a citrate buffered (pH 3.5) solution containing sunitinib. Tumor growth is assessed using tumor volume measurements taken twice a week. When tumors in animals receiving vehicle treatment reach an average size of 1000 mm³ or are determined to negatively impact the animals' quality of life, studies are usually stopped.
Rats: The Wistar rats are adult males weighing between 325 and 349 g. In two drug studies, the efficacy of the time-lapse imaging method in assessing the anti-angiogenic effects of a particular drug treatment is verified. First, mesenteric windows are taken from adult male Wistar rats, and the tissues are cultured for three days in two different experimental groups: 1) 10% serum (n = 8 tissues from 4 rats), and 2) 10% serum + Sunitinib (5 μM; n=8 tissues from 4 rats).

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1. Nude mouse A549 xenograft model: Female athymic nude mice (6–8 weeks old) are subcutaneously injected with 5×10⁶ A549 cells (suspended in 100 μL PBS/Matrigel 1:1) into the right flank. When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and Sunitinib free base (20 mg/kg). The drug is administered by oral gavage once daily for 21 days. Tumor volume (V = length×width²/2) is measured every 3 days, and body weight is monitored [2]
2. SCID mouse MV4-11 AML model: Male SCID mice (7–9 weeks old) are intravenously injected with 1×10⁷ MV4-11 cells. Three days later, mice are divided into 2 groups (n=8/group): vehicle (0.5% methylcellulose) and Sunitinib free base (40 mg/kg, oral gavage once daily for 14 days). Survival is recorded daily, and peripheral blood is collected weekly to detect human CD45-positive cells (disease burden) [5]
3. Rat orthotopic Caki-1 RCC model: Male Wistar rats (200–220 g) are anesthetized, and 1×10⁶ Caki-1 cells are injected into the left kidney capsule. Two weeks after implantation, rats are randomized into 2 groups (n=5/group): vehicle (0.2% Tween 80 in saline) and Sunitinib free base (50 mg/kg, oral gavage once daily for 35 days). Rats are euthanized; primary tumors are excised and weighed, and lung tissues are fixed to count metastatic nodules [6]
4. Mouse laser-induced CNV model: Female C57BL/6 mice (8–10 weeks old) are anesthetized, and laser photocoagulation is applied to the choroid to induce CNV. One day later, mice are divided into 2 groups (n=6/group): vehicle (saline) and Sunitinib free base (15 mg/kg, oral gavage once daily for 10 days). Mice are euthanized, choroidal flat mounts are prepared and stained with isolectin B4, and CNV area is measured with confocal microscopy [1]

Absorption, Distribution and Excretion
Following oral administration, sunitinib typically reaches peak plasma concentration (Cmax) between 6 and 12 hours (Tmax). Food has no effect on the bioavailability of sunitinib. Sunitinib can be taken with or without food. The pharmacokinetic profile of sunitinib was similar in healthy volunteers and in the tested solid tumor populations, including patients with gastrointestinal stromal tumors (GIST) and renal cell carcinoma (RCC). Sunitinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4 to its major active metabolite, which is further metabolized by CYP3A4. Sunitinib is primarily excreted in feces. In the [14C]sunitinib human weight balance study, 61% of the dose was excreted in feces, and 16% was excreted by the kidneys.
2230 L (apparent volume of distribution, Vd/F)
34 - 62 L/h [Total Oral Clearance]
Peak plasma concentrations of sunitinib typically occur within 6-12 hours after oral administration. Food has no effect on the bioavailability of sunitinib.
Steady-state concentrations of sunitinib and its major active metabolite are reached within 10 to 14 days. By day 14, the total plasma concentrations of sunitinib and its active metabolite range from 62.9 to 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or its major active metabolite were observed with repeated daily dosing or repeated dosing cycles in the tested dosing regimens.
Sunitinib and its major active metabolite are 95% and 90% bound to human plasma proteins in vitro, respectively.
The apparent volume of distribution (Vd/F) of sunitinib is 2230 L. Within the dose range of 25-100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose. For more complete data on absorption, distribution, and excretion of sunitinib (11 items in total), please visit the HSDB record page. Metabolism/Metabolites Sunitinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4 to its major active metabolite, which is further metabolized by other enzymes. CYP3A4. Sunitinib is primarily metabolized by the cytochrome P-450 (CYP) isoenzyme 3A4 to several metabolites. The major circulating metabolite is an N-deethyl derivative, which has been shown to have the same potency as sunitinib in biochemical and cellular assays; this metabolite accounts for approximately 23-37% of the total plasma concentration of the drug and is also metabolized by CYP3A4. Sunitinib and its major active metabolite were the main drug-related compounds identified in plasma, urine, and feces, accounting for 91.5%, 86.4%, and 73.8% of the radioactivity in the mixed samples, respectively.
Biological Half-Life

Following a single oral administration in healthy volunteers, the terminal half-lives of sunitinib and its major active metabolite were approximately 40–60 hours and 80–110 hours, respectively.
Following a single oral administration in healthy volunteers, the terminal half-lives of sunitinib or its major active metabolite were approximately 40–60 hours or 80–110 hours, respectively.
1. Rats: After oral administration of sunitinib free base (20 mg/kg), the oral bioavailability (F) was 48%, the peak plasma concentration (Cmax) was 1.2 μg/mL, the time to peak concentration (Tmax) was 1.5 hours, and the terminal half-life (t1/2) was 6.8 hours. After intravenous injection (5 mg/kg), t1/2 was 5.2 hours [1]
2. Dogs: After oral administration of sunitinib free base (10 mg/kg), F=36%, Cmax=0.8 μg/mL, Tmax=2 hours, t1/2=9.5 hours. Plasma protein binding rate>95% (measured by ultrafiltration)[1]
3. Mice: After a single oral administration of sunitinib free base (30 mg/kg), the highest drug concentrations were found in the liver (12 μg/g) and kidneys (8 μg/g) 2 hours after administration; the brain tissue concentration was <0.5 μg/g, indicating poor blood-brain barrier penetration [4]
4. Metabolism: In human liver microsomes, sunitinib free base is metabolized to N-deethylsunitinib (the main active metabolite), with a metabolic clearance rate of 1.2 mL/min/mg protein [1]

Hepatotoxicity
Elevated serum transaminase levels were common in large clinical trials of sunitinib, occurring in 39% of the sunitinib group and 23% of the placebo group. Only 2% to 3% of patients in the sunitinib group (and 1% in the control group) experienced transaminase levels exceeding 5 times the upper limit of normal (ULN). These abnormalities are usually asymptomatic. If enzyme levels are significantly elevated (ALT or AST persistently exceeding 5 times the ULN, or bilirubin exceeding 3 times the ULN), dose adjustment or temporary discontinuation of treatment is recommended, followed by restarting treatment at a lower dose. Sunitinib treatment has also been associated with a higher rate of elevated serum bilirubin, usually mild to moderate, and unrelated to ALT or AST elevations. These changes may be related to the interaction with hepatic UDP-glucuronyl transferase, which is also responsible for bilirubin excretion. More importantly, several cases of clinically significant liver injury have been reported attributable to sunitinib treatment. Onset typically occurs after several treatment cycles. The pattern of elevated serum enzymes is typically hepatocellular, with clinical presentations resembling acute hepatic necrosis. In some cases, the injury may be due to hypotension, shock, or ischemia, rather than direct hepatotoxicity (Case 1). Regardless, the injury can be severe, with several reports of acute liver failure and death. Immune allergic reactions (rash, fever, and eosinophilia) are uncommon. Finally, there have been reports of sunitinib causing hyperammonemia and encephalopathy in cancer patients receiving standard or even low-dose oral therapy (Case 2). Onset is 1 to 3 weeks, presenting with confusion and irritability, mild elevations in serum enzymes and bilirubin, and significantly elevated serum ammonia (4-10 times the upper limit of normal). Recovery is rapid upon discontinuation of sunitinib, but relapse may occur upon re-administration. Notably, cross-reactivity with other tyrosine kinase inhibitors appears to be minimal. Probability score: B (Highly probable cause of clinically evident liver injury, including hyperammonemia syndrome).

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Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the clinical use of sunitinib during lactation. Because sunitinib and its metabolites bind to plasma proteins at a rate exceeding 90%, the levels in breast milk may be very low. However, one of the metabolites has a half-life of up to 110 hours and may accumulate in the infant. The manufacturer recommends discontinuing breastfeeding during sunitinib treatment and for at least 4 weeks after the last dose.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The in vitro binding rates of sunitinib and its major metabolites to human plasma proteins are 95% and 90%, respectively.

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Interaction
…A 57-year-old woman, after failing imatinib treatment, began sunitinib treatment for recurrent metastatic gastrointestinal stromal tumors. After 8 cycles of sunitinib (50 mg/day for 4 weeks, followed by a 2-week break), her condition stabilized and her liver function returned to normal. She continued to take acetaminophen (approximately 4.5 g/week) and her usual asthma medication. In the 8th cycle, she took levothyroxine sodium (50-150 mcg/day) orally for approximately 30 days to control hypothyroidism, after which she began the 9th cycle of sunitinib. On day 4 of the 9th cycle, she was hospitalized due to progressively elevated circulating liver enzyme levels. Despite discontinuing sunitinib and initiating intensive supportive care, she died 4 days after admission. Autopsy revealed severe central lobular necrosis in her liver with moderate to severe steatosis, and minimal tumor invasion of the parenchyma. Viral staining results were negative. Liver failure has been reported in rare cases in patients taking sunitinib. Autopsy results ruled out tumor progression and viral infection as causes of death; the patient likely died from the combined effects of sunitinib, acetaminophen, and levothyroxine. Although sunitinib is only considered a possible hepatotoxic substance (Roussel Uclaf causality assessment method), and may even have a hepatoprotective effect against long-term acetaminophen (a possible hepatotoxic substance) over 48 weeks by inducing localized hypothyroidism within the liver, it is presumed that correcting presupposed hepatic hypothyroidism with oral levothyroxine (a possible hepatotoxic substance) and restarting sunitinib treatment may have induced liver necrosis. …Potential CYP3A4 inhibitors, such as ketoconazole, may increase plasma concentrations of sunitinib. It is recommended to choose an alternative concomitant medication with weak or no enzyme inhibition. In healthy volunteers, a single dose of sunitinib, when combined with the potent CYP3A4 inhibitor ketoconazole, resulted in a 49% and 51% increase in the combined levels of sunitinib and its major active metabolites (Cmax and AUC0-∞), respectively. Concomitant use of sunitinib with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib plasma concentrations. Grapefruit may also increase sunitinib plasma concentrations. CYP3A4 inducers (e.g., rifampin) may decrease sunitinib plasma concentrations. It is recommended to choose an alternative drug with weak or no enzyme-inducing activity. In healthy volunteers, a single dose of sunitinib, when concomitantly used with the potent CYP3A4 inducer rifampin, resulted in a 23% and 46% reduction in the combined values of sunitinib and its major active metabolites (Cmax and AUC0-∞), respectively. Concomitant use of sunitinib with CYP3A4 family inducers (e.g., dexamethasone, phenytoin sodium, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) may decrease sunitinib plasma concentrations. St. John's wort may cause unpredictable decreases in plasma sunitinib concentrations and should therefore be avoided during sunitinib treatment.

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1. Acute toxicity in mice: A single oral dose of sunitinib free base (up to 200 mg/kg) did not result in death within 7 days, but mice in the 150–200 mg/kg group experienced transient weight loss (5–8% reduction within 48 hours) and decreased kinetic activity, which resolved within 7 days [4]
2. Subchronic toxicity in rats (oral administration over 28 days): - 25 mg/kg group: No significant changes in body weight, organ weight, or hematological parameters [6]
- 50 mg/kg group: Mild weight loss (3–5%), slight increase in liver weight (10–12%), and a 15% decrease in platelet count; no histopathological changes were observed in the liver/kidneys [6]
- 100 mg/kg group: Significant weight loss (8–10%), elevated serum ALT (2-fold) and AST (1.8-fold), and severe thrombocytopenia (40% decrease); 2 out of 5 rats showed significant weight loss. Only mild liver necrosis was observed [6]
3. Nude mouse xenotransplantation studies (treatment 21-35 days): Sunitinib free base (20-50 mg/kg) did not cause more than 10% weight loss or significant organ toxicity (as assessed by histopathological evaluation of liver, kidney and spleen) [2][4]

[1]. J Med Chem . 2003 Mar 27;46(7):1116-9.

[2]. Clin Cancer Res . 2003 Jan;9(1):327-37.

[3]. Blood . 2003 May 1;101(9):3597-605.

[4]. Mol Cancer Ther . 2003 Oct;2(10):1011-21.

[5]. Blood . 2004 Dec 15;104(13):4202-9.

[6]. Mol Cancer Ther . 2006 Oct;5(10):2522-30.

[7]. EMBO J . 2011 Mar 2;30(5):894-905.

Therapeutic Uses

Angiogenesis Inhibitor; Antitumor Drug
Sunitinib Malate is indicated for the treatment of gastrointestinal stromal tumors that have progressed or are intolerant to imatinib mesylate. /US Product Label Includes/
Sunitinib Malate is indicated for the treatment of advanced renal cell carcinoma. /US Product Label Includes/
Sunitinib Malate is indicated for the treatment of locally advanced or metastatic unresectable progressive, well-differentiated pancreatic neuroendocrine tumors. /US Product Label Includes/

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Drug Warnings
/Black Box Warning/ Hepatotoxicity—Hepatotoxicity has been observed in clinical trials and postmarketing experience. This hepatotoxicity can be serious, and deaths have been reported. Sunitinib is associated with hepatotoxicity and may lead to liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and postmarketing experience. Signs of liver failure include jaundice, elevated transaminases and/or hyperbilirubinemia, accompanied by encephalopathy, coagulation disorders and/or renal failure. Liver function parameters (ALT, AST, bilirubin) should be monitored before starting treatment, at each treatment cycle, and as clinically necessary. Sunitinib should be discontinued for Grade 3 or 4 drug-related adverse liver events; if the adverse event does not resolve, treatment should be discontinued. Sunitinib should not be restarted if the patient subsequently develops severe changes in liver function parameters or other signs and symptoms of liver failure. The safety of this product has not been established in patients with ALT or AST > 2.5 times the upper limit of normal (ULN) or ALT or AST > 5.0 times the upper limit of normal (ULN) due to liver metastasis. Post-marketing experience suggests that this product can cause cardiovascular events, including heart failure, myocardial disease, and cardiomyopathy, some of which are fatal. In randomized trials, among patients receiving sunitinib for metastatic renal cell carcinoma, 21% had a left ventricular ejection fraction (LVEF) below the lower limit of normal, and 4% had a decreased LVEF (below 50% or more than 20% from baseline). In patients treated with sunitinib, 1% reported left ventricular dysfunction and less than 1% reported congestive heart failure. For more complete data on sunitinib warnings (33 in total), please visit the HSDB record page. Pharmacodynamics Sunitinib is an oral small-molecule multi-target receptor tyrosine kinase (RTK) inhibitor approved by the FDA on January 26, 2006. 1. The free base of sunitinib exerts its antitumor effect through two mechanisms: by blocking the VEGFR/PDGFR signaling pathway to inhibit angiogenesis, and by directly inhibiting the proliferation of tumor cells expressing c-Kit/FLT3 [1][3]. 2. Its major active metabolite (N-desethylsunitinib) has similar kinase inhibitory activity to the parent drug (IC50 for VEGFR2: 5–12 nM). It accounts for approximately 30% of the total activity in vivo [1]
3. In preclinical models, sunitinib free base showed synergistic antitumor activity when used in combination with docetaxel (lung cancer) and gemcitabine (pancreatic cancer); the combination therapy reduced tumor volume by an additional 20-30% compared with monotherapy [7]
4. Sunitinib free base was effective against tumor models resistant to other anti-angiogenic drugs (e.g., A549 xenograft tumors resistant to bevacizumab), with a tumor growth inhibition rate (TGI) of approximately 60%, compared to approximately 25% for bevacizumab [2]
5. Sunitinib has higher selectivity for tumor-associated kinases (VEGFR, PDGFR) than for housekeeping kinases (e.g., EGFR, Src), thereby reducing off-target toxicity and giving it good preclinical safety [1]

C22H27FN4O2

398.47

398.211

C, 66.31; H, 6.83; F, 4.77; N, 14.06; O, 8.03

557795-19-4

Sunitinib Malate;341031-54-7;Sunitinib-d10;1126721-82-1;Sunitinib-d4;1126721-79-6; 342641-94-5; 1275588-72-1 (mesylate) ; 1126641-10-8; 1327155-72-5 (HCl); 1221149-36-5 (acetate); 1332306-95-2 (oxalate)

5329102

Yellow solid powder

1.2±0.1 g/cm3

572.1±50.0 °C at 760 mmHg

189-191ºC

299.8±30.1 °C

0.0±1.6 mmHg at 25°C

1.611

3.15

77.23

3

4

7

29

636

0

FC1C=C2C(NC(=O)/C/2=C\C2NC(C)=C(C(NCCN(CC)CC)=O)C=2C)=CC=1

WINHZLLDWRZWRT-ATVHPVEESA-N

InChI=1S/C22H27FN4O2/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28)/b17-12-

N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

SU11248; SU 11248; sunitinibum; Su-011248; Sunitinib Base; SU011248; SU-11248; sunitinib; trade name: Sutent.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 1.11 mg/mL (2.79 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 11.1 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 1.11 mg/mL (2.79 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 11.1 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 5% DMSO+corn oil: 7mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。