Exemestane (FCE 24304; EXE)   中文名称: 依西美坦

Aromatase (IC50s = 30 nM)

Exemestane 可显着增加 hFOB、Saos-2 细胞中的细胞数量（1-1000 nM；72 小时）[2]。 Exemestane (72 h) 刺激 hFOB 细胞中 MYBL2、OSTM1、HOXD11、ADCYAP1R1 和磷脂酰肌醇蛋白聚糖 2 的表达，并增强 Saos-2 和 hFOB 细胞中的碱性磷酸酶活性 [2]。依西美坦的 Ki 值为 4.3 nM，以时间依赖性方式竞争性抑制和灭活人胎盘芳香酶。依西美坦的 IC50 为 0.9 μM，可替代大鼠前列腺雄激素受体中的 [3H]5α-二氢睾酮 [1]。

依西美坦治疗（20-100 mg/kg；肌肉注射；每周一次；持续 16 周）导致小梁骨体积、第五腰椎抗压强度、股骨弯曲强度以及腰椎和股骨 BMD 显着增加。依西美坦可显着降低卵巢切除术引起的血清骨钙素和吡啶啉的升高。依西美坦可显着降低血清胆固醇和低密度脂蛋白胆固醇[3]。当皮下暴露于依西美坦（20 mg/kg/天）时，患有由 7,12-二甲基苯并蒽 (DMBA) 产生的乳腺肿瘤的大鼠显示出 26% 的完全消退 (CR) 和 18% 的部分 (PR) 肿瘤消退 [4]。

芳香化酶抑制剂和5α还原酶抑制剂可分别用于绝经后乳腺癌症和良性前列腺增生症的治疗。FCE 27993是一种与依西美坦结构相关的新型甾体不可逆芳香化酶抑制剂（FCE 24304）。发现该化合物是人胎盘芳香化酶的非常有效的竞争性抑制剂，Ki为7.2 nM（依西美坦为4.3 nM）。在胎盘芳香化酶的预孵育研究中，发现FCE 27993与依西美坦一样，以更高的失活率（t1/2 4.5 vs 15.1分钟）和类似的Ki（inact）（56 vs 66 nM）引起时间依赖性抑制。发现该化合物对雄激素受体的结合亲和力非常低（二氢睾酮的RBA为0.09%），与依西美坦相比，在未成熟去势大鼠中，皮下注射不具有高达100mg/kg/天的雄激素活性。在一系列具有氟取代-17β-酰胺侧链的新型4-氮杂甾体化合物中，有三种化合物，即FCE 28260、FCE 28175和FCE 27837，被鉴定为前列腺5α还原酶的体内外有效抑制剂。发现它们的IC50值对人类酶的抑制分别为16、38和51 nM，对大鼠酶的抑制则分别为15、20和60 nM[1]。

细胞活力测定[2]
细胞类型： hFOB、Saos-2 细胞
测试浓度： 1 nM、10 nM、100 nM、1000 nM
孵育持续时间：72小时
实验结果：诱导细胞增殖。

Animal/Disease Models: Female Sprague Dawley rats (10-month-old) bearing ovariectomy [3]
Doses: 20 mg/kg, 50 mg/kg, or 100 mg/kg
Route of Administration: intramuscular (im) injection; once weekly; for 16 weeks
Experimental Results: Dramatically increased the lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume.

Absorption, Distribution and Excretion
42%
Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.
The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.
Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng·hr/mL) were about twice those in healthy women (41.4 ng·hr/mL).
Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and (alpha) 1 -acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.
For more Absorption, Distribution and Excretion (Complete) data for EXEMESTANE (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

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Biological Half-Life
24 hours
Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours.
... The terminal half-life was 8.9 hr. Maximal estradiol suppression of 62 +/- 14% was observed at 12 hr.

Hepatotoxicity
Serum enzymes are reported to be elevated in 4% to 11% of women treated with exemestane, but these elevations are usually mild, asymptomatic and self-limited, rarely requiring dose modification. There have been very rare instances of clinically apparent liver injury associated with exemestane therapy, typically arising withinone to four months of starting treatment and typically presenting with a cholestatic pattern of enzyme elevations. Immunoallergic features (fever, rash, eosinophilia) are uncommon as are autoantibody formation. Some instances have been severe with signs of hepatic failure, but most cases were self-limited. Unlike tamoxifen, exemestane has not been associated with development of fatty liver disease, steatohepatitis or cirrhosis.
Likelihood score: C (probable 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 use of exemestane during breastfeeding. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. The manufacturer recommends that breastfeeding be discontinued during exemestane therapy and for 1 month after 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
90% (mainly α1-acid glycoprotein and albumin)

[1]. Novel aromatase and 5 alpha-reductase inhibitors. J Steroid Biochem Mol Biol, 1994. 49(4-6): p. 289-94.

[2]. Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2004 Sep 1;10(17):5717-23.

[3]. Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res, 2004. 10(17): p. 5717-23.

[4]. Zaccheo, T., D. Giudici, and E. Di Salle, Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats. J Steroid Biochem Mol Biol, 1993. 44(4-6): p. 677-80.

Description
Exemestane is a 17-oxo steroid that is androsta-1,4-diene-3,17-dione in which the hydrogens at position 6 are replaced by a double bond to a methylene group. A selective inhibitor of the aromatase (oestrogen synthase) system, it is used in the treatment of advanced breast cancer. It has a role as an EC 1.14.14.14 (aromatase) inhibitor, an antineoplastic agent, an environmental contaminant and a xenobiotic. It is a 17-oxo steroid and a 3-oxo-Delta(1),Delta(4)-steroid. It derives from a hydride of an androstane.
Exemestane is an oral steroidal aromatase inhibitor used in the adjuvant treatment of hormonally-responsive (also called hormone-receptor-positive, estrogen-responsive) breast cancer in postmenopausal women. It irreversibly binds to the active site of the enzyme resulting in permanent inhibition.
Exemestane is an Aromatase Inhibitor. The mechanism of action of exemestane is as an Aromatase Inhibitor.
Exemestane is a steroidal inhibitor of aromatase which effectively blocks estrogen synthesis in postmenopausal women and is used as therapy of estrogen receptor positive breast cancer, usually after resection and after failure of tamoxifen. Exemestane has been associated with a low rate of serum enzyme elevations during therapy and rare instances of clinically apparent liver injury.
Exemestane is an irreversible steroidal aromatase inhibitor, with antiestrogen and antineoplastic activities. Upon oral administration, exemestane binds irreversibly to and inhibits the enzyme aromatase, thereby blocking the peripheral aromatization of androgens, including androstenedione and testosterone, to estrogens. This lowers estrogen levels in the blood circulation.

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Drug Indication
For the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
FDA Label

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Mechanism of Action
Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It irreversibly binds to the active site causing permanent inhibition necessitating de novo synthesis to restore enzymatic function. Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on the adrenal biosynthesis of corticosteroids or aldosterone. This reduction in serum and tumor concentrations of estrogen delays tumor growth and disease progression. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
... exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors...
Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
... Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total aromatase inhibition in vivo with the use of a steroidal aromatase inhibitor. The observation that exemestane is a highly potent aromatase inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer.
... Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S(35)-methionine was used to determine the half-life (t(1/2)) of aromatase protein. In the presence of 200 nmol/L exemestane, the t(1/2) of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. ...

C20H24O2

296.4

296.177

C, 81.04; H, 8.16; O, 10.80

107868-30-4

Exemestane (Standard);107868-30-4;Exemestane-d2;Exemestane-13C3;Exemestane-d3

60198

... white to slightly yellow crystalline powder

1.1±0.1 g/cm3

453.7±45.0 °C at 760 mmHg

155.13°C

169.0±25.7 °C

0.0±1.1 mmHg at 25°C

1.572

3.11

34.14

0

2

0

22

653

5

O=C1C([H])([H])C([H])([H])[C@]2([H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])[C@]1([H])[C@]3(C([H])=C([H])C(C([H])=C3C(=C([H])[H])C([H])([H])[C@@]21[H])=O)C([H])([H])[H]

BFYIZQONLCFLEV-DAELLWKTSA-N

InChI=1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1

(8R,9S,10R,13S,14S)-10,13-dimethyl-6-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione.

FCE24304, PNU155971; PNU155971; PNU-155971; PNU 155971; FCE24304; FCE-24304; FCE 24304; Exemestane; US trade name: Aromasin.

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: ≥ 2.5 mg/mL (8.43 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 (8.43 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 25.0 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: ≥ 2.5 mg/mL (8.43 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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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。