Bosutinib (SKI-606) 的 IC50 值在低纳摩尔范围内，是多种慢性粒细胞白血病细胞系中 Bcr-Abl 的有效抑制剂[2]。

在裸鼠中，布舒替尼（口服管饲；75 mg/kg，每日两次或 150 mg/kg，每日一次）具有抗人 KU812 异种移植物作用。伯舒替尼（150 mg/kg；每天一次，每周五天）具有针对同基因 Bcr-Abl WT 和突变 Ba/F3 异种移植物的活性[2]。

细胞增殖测定[2]
细胞类型：白血病 Bcr-Abl+ 细胞系（KCL22、K562、KU812 和 Lama84）
测试浓度： 0.1 μmol/L
孵育时间： 72 小时
实验结果： 抑制多种人 CML 衍生细胞系，IC50 值范围为 1 至 20 nmol/L

Animal/Disease Models: KU812CM L xenograft model[2]
Doses: 75 mg/kg twice (two times) daily or 150 mg/kg one time/day
Route of Administration: Bosutinib (po (oral gavage); 75 mg/kg twice (two times) daily or 150 mg/kg one time/day)
Experimental Results: Had the therapeutic activity and produced a dose- and schedule-dependent weight loss.

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Animal/Disease Models: Syngeneic Bcr-Abl WT and mutant Ba/F3 xenografts[2]
Doses: 150 mg/kg
Route of Administration: Bosutinib (150 mg/kg; one time/day, 5 days weekly)
Experimental Results: diminished the rate of tumor growth and prolonged event-free survival of mice.

Absorption, Distribution and Excretion
Bosutinib exhibits dose-proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady-state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg. Bosutinib steady-state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of bosutinib at the same dose, under fed conditions. The median bosutinib (minimum, maximum) tmax was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects. Bosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories.
Following a single oral dose of [¹⁴C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose was recovered in urine.
The mean (SD) apparent bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib.
The mean (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib.

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Metabolism / Metabolites
Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive.

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Biological Half-Life
The mean (SD) bosutinib terminal phase elimination half-life (t^1/2) was 22.5 ± 1.7 hours following a single oral dose of bosutinib.

Hepatotoxicity
In large clinical trials of bosutinib, elevations in serum aminotransferase levels were common, occurring in up to 58% of bosutinib treated patients. Values greater than 5 times the upper limit of normal (ULN) occurred in 4% to 19% of bosutinib recipients (and 3% of imatinib treated subjects). These abnormalities were usually asymptomatic, but led to discontinuation of therapy in up to 2% of treated patients. In addition, there have been isolated reports of clinically apparent liver injury attributed to bosutinib therapy, although the frequency of this outcome and the clinical features of the injury have not been well defined. The time to onset has generally been within 3 months and the pattern of serum enzyme elevations was usually hepatocellular.
Certainly other tyrosine kinase receptor inhibitors used in the therapy of CML such as imatinib, nilotinib and ponatinib have been associated with cases of acute liver injury with jaundice. With these agents, the liver injury typically arises after several months of therapy and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features (rash, fever and eosinophilia) and autoantibody formation are usually not present.
Reactivation of hepatitis B has been reported with imatinib and nilotinib therapy, but not with bosutinib. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir. Whether reactivation occurs with bosutinib therapy is unclear.
Likelihood score: D (possible uncommon cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of bosutinib during breastfeeding. Because bosutinib is 96% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 22 hours and it might accumulate in the infant. National Comprehensive Cancer Network guidelines recommend avoiding breastfeeding during bosutinib therapy and the manufacturer recommends withholding breastfeeding until 2 weeks following the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Bosutinib protein binding is 94% in vitro and 96% ex vivo and is independent of concentration.

[1]. Jorge E Cortes, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92.
[2]. Miriam Puttini, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006 Dec 1;66(23):11314-22.

Pharmacodynamics
A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.

C26H29CL2N5O3

530.45

529.164

380843-75-4

Bosutinib hydrate;918639-08-4;Bosutinib-d8;Bosutinib isomer;1391063-17-4

5328940

White to yellow solid powder

1.4±0.1 g/cm3

649.7±55.0 °C at 760 mmHg

116-120ºC

346.7±31.5 °C

0.0±1.9 mmHg at 25°C

1.652

5.48

82.88

1

8

9

36

734

0

ClC1=C([H])C(=C(C([H])=C1N([H])C1=C(C#N)C([H])=NC2=C([H])C(=C(C([H])=C21)OC([H])([H])[H])OC([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])OC([H])([H])[H])Cl

UBPYILGKFZZVDX-UHFFFAOYSA-N

InChI=1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)

4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile

Bosutinib; SKI606; SKI 606; SK-I606; trade name: Bosulif.

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: ≥ 2.5 mg/mL (4.71 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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: ≥ 2.5 mg/mL (4.71 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (3.92 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 4 中的溶解度: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10 mg/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。