17α-hydroxylase (IC50 = 2.5 nM); 17,20-lyase (IC50 = 15 nM)

醋酸阿比特龙 (Abi) 是抗癌药物阿比特龙的酯前药，17,20-裂解酶和 17α-羟化酶（CYP17 是双功能酶）的 IC50 值，17,20-裂解酶和 17α-羟化酶活性为 15 nM，分别为 2.5 nM。阿比特龙对人 17,20-裂解酶的 IC50 为 27 nM，对 17α-羟化酶抑制的 IC50 为 30 nM[1]。研究表明，剂量≥5μM的阿比特龙可以显着抑制AR阳性前列腺癌细胞系LNCaP和VCaP的增殖[2]。阿比特龙的竞争性 Ki 值为 2.1 和 8.8 μM，可抑制重组人 3βHSD1 和 3βHSD2 的活性。在这两种细胞系中，10 μM 阿比特龙可以完全抑制 5α-二酮和 DHT 的产生。在迅速扩大的亚组中，比拉特龙治疗显着减缓了 CRPC 的进展，在整个 4 周治疗期间有效抑制了肿瘤生长 (P<0.00001) [3]。

在对去势有抵抗力的前列腺癌中，醋酸比拉特龙 (Abi) 可以提高生存率 (CRPC)。阿比特龙已被证明具有 0.5 mmol/kg/d 的抑制剂量，导致血清浓度约为 0.5 至 1 μM。它抑制 LNCaP 中 [3H]-脱氢表雄酮 (DHEA) 的消耗和 Δ4-雄烯二酮 (AD) 的积累，IC50<1 μM。对照组的异种移植肿瘤表现出广泛的生长速度，有些生长缓慢，只有少数表现出旺盛的生长[3]。

酶化验[3]
abiraterone作为抑制剂的孵育实验包含重组人3βHSD1或3βHSD2(在酵母微粒体中，每次孵育分别为3.2或25 μg蛋白)，[3H]-孕烯醇酮(100,000 cpm, 1 - 20 μmol/L)， abiraterone (5-20 μmol/L)或乙醇载体在0.2 ~ 1ml磷酸钾缓冲液中。37℃预孵育1 ~ 3分钟后，加入NAD+ (1 mmol/L)， 37℃孵育15分钟。加入1 ~ 2ml乙酸乙酯:异辛烷(1:1)停止反应，提取类固醇到有机相。干燥后的提取物用薄层色谱(TLC)在塑料背衬硅胶板上用3:1氯仿:乙酸乙酯或高效液相色谱(HPLC)进行分离。对于薄层色谱，用碘蒸气鉴定含有类固醇的板的区域，用剪刀切除，并按所述用液体闪烁计数定量。HPLC法采用BioSafeII闪烁鸡尾酒法测定孕烯醇酮的放射性。以阿比特龙作为底物进行孵育，但以0.1 ~ 5 μmol/L未标记的阿比特龙代替孕烯醇酮，并采用HPLC定量转化。

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配体结合试验[2]
将转染WT或T877A突变体AR或LNCaP细胞的PC-3细胞接种于24孔板中，在添加了css的无酚红培养基中培养24小时。为了确定[3H]-R1881与WT和T877A AR结合的动力学，将细胞用0.25-25nM [3H]-R1881处理2小时，然后洗涤、裂解并测量放射性。Kd和Bmax采用Graphpad Prism™软件非线性回归测定。当[3H]-R1881在WT和T877A AR突变体转染中达到几乎饱和AR所需的浓度(5nM)时，测定被试化合物对[3H]-R1881的置换。采用非线性回归法确定了[3H]-R1881置换50%时的浓度(EC50)。

细胞生存能力[2]
LNCaP和VCaP细胞分别接种于96孔板中，在添加css的不含酚红或添加fbs的培养基中培养7 d。分别于24小时和96小时用化合物处理细胞，第7天通过添加CellTiter Glo和测量发光来测定细胞活力。

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荧光素酶报告基因检测[2]
我们构建了一个PSA-ARE3-luc荧光素酶报告质粒，该质粒与人类AR表达质粒F527-AR(野生型(WT)或突变型)共转染;测序证实的突变)转化为PC-3细胞。将这些细胞播种在白色不透明的384孔板中，在添加10% css的不含酚红的RPMI 1640中生长30小时。然后用指定浓度的化合物和R1881处理细胞16小时。荧光素酶活性通过加入ONE Glo并在TopCount平板阅读器上测量发光来测定。转染效率和蛋白表达见补充图1。

Mouse xenograft studies[4]
Male NOD/SCID mice 6 to 8 weeks of age were used, and studies were conducted under an Institutional Animal Care and Use Committee–approved protocol. Mice were surgically orchiectomized and implanted with a 5 mg 90-day sustained release DHEA pellet to mimic CRPC with human adrenal physiology. Two days later, 7 × 106 LAPC4 cells were injected subcutaneously with Matrigel. Tumor dimensions were measured 2 to 3 times per week, and volume was calculated as length × width × height × 0.52. Once tumors reached 300 mm3, mice were randomly assigned to vehicle or Abiraterone treatment groups. Mice in the Abiraterone group were treated with 5 mL/kg intraperitoneal injections of 0.5 mmol/kg/d (0.1 mL 5% benzyl alcohol and 95% safflower oil solution) and control mice with vehicle only, once daily for 5 days per week over a duration of 4 weeks (n = 8 mice per treatment). Statistical significance between Abiraterone and vehicle treatment groups was assessed by ANOVA based on a mixed-effect model.

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Dissolved in 0.1 mL 5% benzyl alcohol and 95% safflower oil solution; 0.5 mmol/kg/d; s.c. injection

Male NOD/SCID mice with LAPC4 cells

Absorption
Geometric mean (± SD) Cmax was 73 (± 44) ng/mL and AUC0-∞ was 373 (± 249) ng x hr/mL following a single dose of 500 mg abiraterone acetate in overnight-fasted healthy subjects. Dose proportionality was observed in single doses of abiraterone acetate ranging from 125 mg to 625 mg. A group of patients with mCRPC received a daily dose of 1,000 mg: at steady-state, the mean (± SD) Cmax was 226 (± 178) ng/mL and AUC was 993 (± 639) ng x hr/mL. Following oral administration of abiraterone acetate to patients with metastatic castration-resistant prostate cancer, the median Tmax was two hours. _In vivo_, abiraterone acetate is converted to abiraterone. In clinical studies of other abiraterone acetate formulations, abiraterone acetate plasma concentrations were below detectable levels (< 0.2 ng/mL) in > 99% of the analyzed samples. Systemic exposure to abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax was approximately 6.5-fold higher, and AUC0-∞ was 4.4-fold higher when a single dose of abiraterone acetate 500 mg was administered with a high-fat meal (56-60% fat, 900-1,000 calories) compared to overnight fasting in healthy subjects. Given the normal variation in the content and composition of meals, taking abiraterone with meals has the potential to result in increased and highly variable exposures.

Route of Elimination
Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces: the major compounds present in feces are unchanged abiraterone acetate and abiraterone, accounting for approximately 55% and 22% of the administered dose, respectively. Approximately 5% of the dose is recovered in urine.

Volume of Distribution
The mean (± SD) apparent steady-state volume of distribution is 19,669 (± 13,358) L.

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Metabolism / Metabolites The conversion of abiraterone acetate to abiraterone, the active metabolite, is likely to be mediated by esterases, although specific esterases have not been identified. In human plasma, the two main circulating metabolites are abiraterone sulfate, which is formed by CYP3A4 and SULT2A1, and N-oxide abiraterone sulfate, which is formed by SULT2A1. These metabolites each account for about 43% of abiraterone exposure and are pharmacologically inactive.

Abiraterone has known human metabolites that include abiraterone sulfate. S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

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Biological Half-Life
In patients with mCRPC, the mean (± SD) terminal half-life of abiraterone in plasma is 12 (± 5) hours.

Hepatotoxicity
Serum aminotransferase elevations occur in up to 13% of patients treated with abiraterone compared with 1% to 8% receiving placebo or a comparator drug, but the abnormalities are generally mild, transient and not associated with symptoms or jaundice. ALT elevations above 5 times the upper limit of normal (ULN) occur in 6% of abiraterone treated vs

Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Protein Binding
Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein.

[1]. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014 May-Jun;16(3):387-400.

[2]. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012 May 1;72(9):2176-82.

[3]. Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res. 2012 Jul 1;18(13):3571-9.

[4]. Intracrine androgen biosynthesis in renal cell carcinoma. Br J Cancer. 2017 Mar 28;116(7):937-943.

[5]. Hormonal impact of the 17α-hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. British Journal of Cancervolume 90, pages2317–2325 (2004).

Abiraterone acetate can cause developmental toxicity, female reproductive toxicity and male reproductive toxicity according to state or federal government labeling requirements.
Abiraterone acetate is a sterol ester obtained by formal condensation of the 3-hydroxy group of abiraterone with the carboxy group of acetic acid. A prodrug that is converted in vivo into abiraterone. Used for treatment of metastatic castrate-resistant prostate cancer. It has a role as a prodrug, an antineoplastic agent and an EC 1.14.99.9 (steroid 17alpha-monooxygenase) inhibitor. It is a sterol ester and a member of pyridines. It is functionally related to an abiraterone.
Abiraterone Acetate is an orally active acetate ester form of the steroidal compound abiraterone with antiandrogen activity. Abiraterone inhibits the enzymatic activity of steroid 17alpha-monooxygenase (17alpha-hydrolase/C17,20 lyase complex), a member of the cytochrome p450 family that catalyzes the 17alpha-hydroxylation of steroid intermediates involved in testosterone synthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenals to castrate-range levels.
An androstene derivative that inhibits STEROID 17-ALPHA-HYDROXYLASE and is used as an ANTINEOPLASTIC AGENT in the treatment of metastatic castration-resistant PROSTATE CANCER.
See also: Abiraterone (has active moiety); Niraparib; abiraterone acetate (component of) ... View More ...

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Drug Indication
Abiraterone Mylan is indicated with prednisone or prednisolone for: the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT). the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel based chemotherapy regimen.
Abiraterone Krka is indicated with prednisone or prednisolone for: the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see section 5. 1)the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5. 1)the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.
Zytiga is indicated with prednisone or prednisolone for: the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicatedthe treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel based chemotherapy regimen.

C26H33NO2

391.55

391.251

C, 79.76; H, 8.50; N, 3.58; O, 8.17

154229-18-2

Abiraterone;154229-19-3;Abiraterone acetate (Standard);154229-18-2;Abiraterone acetate-d4

9821849

White to off-white solid powder

1.1±0.1 g/cm3

506.7±50.0 °C at 760 mmHg

127-130°C

260.2±30.1 °C

0.0±1.3 mmHg at 25°C

1.584

6.55

39.19

0

3

3

29

739

6

CC(=O)O[C@H]1CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3CC=C2C1)CC=C4C5=CN=CC=C5)C)C

UVIQSJCZCSLXRZ-HMMZIKKISA-N

InChI=1S/C26H33NO2/c1-17(28)29-20-10-12-25(2)19(15-20)6-7-21-23-9-8-22(18-5-4-14-27-16-18)26(23,3)13-11-24(21)25/h4-6,8,14,16,20-21,23-24H,7,9-13,15H2,1-3H3/t20-,21?,23?,24?,25-,26+/m0/s1

[(3S,10R,13S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate

Abiraterone Acetate; CB7630; CB 7630 ; CB-7630; trade name: Zytiga; Yonsa; UNII-EM5OCB9YJ6;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 mg/mL (2.55 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 10.0 mg/mL澄清DMSO储备液加入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: ≥ 1 mg/mL (2.55 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 10.0 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 3 中的溶解度: ≥ 1 mg/mL (2.55 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 10.0 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 4 中的溶解度: 5% DMSO+95% Corn oil: 30mg/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。