Aminoglutethimide (BA-16038)   中文名称: 氨鲁米特

体外活性：氨基鲁米特在体外用人胎盘芳香酶测定时表现出芳香酶抑制作用，芳香酶是一种参与雄激素转化为雌激素的酶，也是乳腺癌内分泌治疗的重要靶点。 Aminogluthimide 以时间依赖性方式抑制绵羊肾上腺皮质细胞中 ACTH 受体 (ACTH-R) mRNA 的表达。与对照细胞相比，氨基鲁米特以剂量依赖性方式显着抑制类固醇分泌和基线 ACTH-R mRNA 表达（300 μM AG，5±1%；30 μM AG，64±1%；3 μM AG，108±19%） , 100±11%) 通过影响基因表达或通过影响 RNA 稳定性来减少转录物积累，在人 NCI-h295 肾上腺皮质癌细胞系中，该细胞系表达功能性 ACTH 受体并产生糖皮质激素、盐皮质激素和雄激素途径的类固醇。 Aminogluthimide 以剂量依赖性方式抑制芳香酶，在 6 个乳腺肿瘤匀浆中的 IC50 为 13 μM，胎盘芳香酶的 IC50 为 6 μM，下丘脑芳香酶的 IC50 为 8 μM。激酶测定：微粒体蛋白 (30 μg)、[1β-3H]雄烯二酮 (6.6 × 105 dpm) 和 NADPH (270 μM) 用于浓度响应实验，孵育时间为 20 分钟。氨基鲁米特最初在 10 μM 和 100 μM 浓度下进行测试，然后使用至少 8 个浓度（从 0.01 μM 到 160 μM）进行完整的浓度-反应研究。对于初始速度研究，[1β-3H]雄烯二酮的浓度在 7.5 至 100 nM 之间变化，孵育时间设置为 5 分钟。通过液体闪烁计数对氚化底物[1β-3H]雄烯二酮转化为雌酮过程中形成的氚化水进行定量。每个测定重复进行三次，并通过非线性回归分析处理结果，从而确定半数最大抑制浓度（IC50）。细胞测定：NCI-h295 肿瘤细胞系维持在补充有转铁蛋白 (0.1 mg/mL)、胰岛素 (5 μg/mL)、硒 (5.2 μg/mL) 和 2% FCS 的 RPMI 1640 培养基中。将细胞与氨基鲁米特（3、30、300 μM）一起孵育 48 小时。然后通过台盼蓝染色检查细胞的细胞活力，并用库尔特计数器进行计数。为了评估 ACTH-R mRNA，收获细胞，提取总 RNA，进行电泳、印迹并与人 ACTH-R cDNA 探针杂交。

服用氨鲁米特1至2周后，氨鲁米特加速其自身代谢，从基础值2.6±0.3（SE）升/24小时增加至5.3±1.4升/24小时，并显着加速合成糖皮质激素和地塞米松的代谢，从施用氨基鲁米特2周后，基础值为145±26.6升/24小时至568±127升/24小时(p < 0.02)。 Aminogluthimide (150 mg/kg) 消除鸟氨酸脱羧酶 (ODC) 的诱导，几乎耗尽成年雌性小鼠卵巢和未成熟雄性小鼠睾丸中由人绒毛膜促性腺激素 (hCG) 引起的性腺和血浆黄体酮或睾酮，这与 cAMP 依赖性蛋白激酶的抑制 (IC50 287 μM) 有关，而不是与类固醇生成途径的阻断有关。

Absorption, Distribution and Excretion
Rapidly and completely absorbed from gastrointestinal tract. The bioavailability of tablets is equivalent to equal doses given as a solution.
After ingestion of a single oral dose, 34%-54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.
Cytadren is rapidly and completely absorbed after oral administration. In 6 healthy male volunteers, maximum plasma levels of Cytadren averaged 5.9 ug/mL at a medium of 1.5 hours after ingestion of 250 mg tablets. The bioavailability of tablets is equivalent to equal doses given as a solution.
Aminoglutethimide crosses the placenta ...
It is not known weather aminoglutethimide is distributed into breast milk.
After ingestion of a single oral dose, 34% to 54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.
For more Absorption, Distribution and Excretion (Complete) data for AMINOGLUTETHIMIDE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic. 34-54% of the administered dose is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as an N-acetyl derivative.
Hepatic; the major metabolite is N-acetylaminoglutethimide; there may be genetic variation among individuals in the rate of acetylation.
Four ... metabolites of aminoglutethimide have been identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, namely 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. ... These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. However, 5-hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro, and therefore, like other metabolites so far described, is an inactivation product of the drug.
Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide.
Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 hr urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily).
Extensive metabolism occurred in all species, with N-acetylaminoglutethimide being the major metabolite except for dog and man. In the latter two species unchanged drug was the main product excreted. A metabolite, 3-(4-acetamidophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, not previously found in human urine, was identified. Chronic administration of aminoglutethimide to rats produced no detectable change in the excretory or metabolite patterns of the drug. However chronic administration of phenobarbitone decreased the urinary excretion of (14)C over a 72 hr period. Residual (72 hr) tissue levels of (14)C were less than 1 microgram equivalent of (14)C-aminoglutethimide/g tissue in the rat, guinea-pig and rabbit. Dog tissues retained a considerable quantity of (14)C at this time.
Hepatic. 34-54% of the administered dose is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as an N-acetyl derivative.
Route of Elimination: After ingestion of a single oral dose, 34%-54% is excreted in the urine as unchanged drug during the first 48 hours, and an additional fraction as the N-acetyl derivative.
Half Life: 12.5 ± 1.6 hours

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Biological Half-Life
12.5 ± 1.6 hours
12.5 hours; reduced to 7 hours after prolonged (2 to 32 weeks) treatment because aminoglutethimide induces hepatic enzymes and accelerates its own metabolism.

Protein Binding
21-25%

Eur J Med Chem.2009 Oct;44(10):4121-7;Cancer Res.1982 Aug;42(8 Suppl):3353s-3359s.

Description
Aminoglutethimide can cause developmental toxicity according to state or federal government labeling requirements.
Aminoglutethimide is a dicarboximide that is a six-membered cyclic compound having ethyl and 4-aminophenyl substituents at the 3-position. It has a role as an antineoplastic agent, an adrenergic agent, an EC 1.14.14.14 (aromatase) inhibitor and an anticonvulsant. It is a dicarboximide, a member of piperidones and a substituted aniline. It is functionally related to a piperidine-2,6-dione.
An aromatase inhibitor that produces a state of "medical" adrenalectomy by blocking the production of adrenal steroids. It also blocks the conversion of androgens to estrogens. Aminoglutethimide has been used in the treatment of advanced breast and prostate cancer. It was formerly used for its weak anticonvulsant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p454)
Aminoglutethimide is an Adrenal Steroid Synthesis Inhibitor. The mechanism of action of aminoglutethimide is as an Adrenal Steroid Synthesis Inhibitor.
Aminoglutethimide has been reported in Broussonetia papyrifera with data available.
Aminoglutethimide is a synthetic derivative of the sedative and anticonvulsant glutethimide with anti-steroid properties. Originally used as an anticonvulsant, aminoglutethimide also blocks adrenal steroidogenesis by inhibiting the enzymatic conversion of cholesterol to pregnenolone. In addition, this agent blocks the peripheral aromatization of androgenic precursors to estrogens. Aminoglutethimide does not suppress ovarian estrogen production.
An aromatase inhibitor that produces a state of 'medical' adrenalectomy by blocking the production of adrenal steroids. It also blocks the conversion of androgens to estrogens. Aminoglutethimide has been used in the treatment of advanced breast and prostate cancer. It was formerly used for its weak anticonvulsant properties.
An aromatase inhibitor that is used in the treatment of advanced BREAST CANCER.

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Drug Indication
For the suppression of adrenal function in selected patients with Cushing's syndrome, malignant neoplasm of the female breast, and carcinoma in situ of the breast.
FDA Label

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Mechanism of Action
Aminoglutethimide reduces the production of D5-pregnenolone and blocks several other steps in steroid synthesis, including the C-11, C-18, and C-21 hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens, mediated through the binding of aminoglutethimide to cytochrome P-450 complexes. Specifically, the drug binds to and inhibits aromatase which is essential for the generation of estrogens from androstenedione and testosterone. A decrease in adrenal secretion of cortisol is followed by an increased secretion of pituitary adrenocorticotropic hormone (ACTH), which will overcome the blockade of adrenocortical steroid synthesis by aminoglutethimide. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of hydrocortisone. Since aminoglutethimide increases the rate of metabolism of dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid replacement. Although aminoglutethimide inhibits the synthesis of thyroxine by the thyroid gland, the compensatory increase in thyroid-stimulating hormone (TSH) is frequently of sufficient magnitude to overcome the inhibition of thyroid synthesis due to aminoglutethimide. In spite of an increase in TSH, aminoglutethimide has not been associated with increased prolactin secretion.
Aminoglutethimide produces suppression of the adrenal cortex by inhibiting enzyme conversion of cholesterol to pregnenolone, thus blocking synthesis of adrenal steroid; it may also affect other steps in the synthesis and metabolism of these steroids. A compensatory increase in secretion of adrenocorticotropic hormone (ACTH by the pituitary occurs (except in patients with ACTH-independent adenomas or carcinomas), necessitating glucocorticoid administration to maintain aminoglutethimide's effect. Aminoglutethimide also inhibits estrogen production from androgens in peripheral tissues by blocking the aromatase enzyme. An additional mechanism in breast cancer, involving enhanced metabolism of estrone sulfate, has also been proposed.
Cytadren blocks several other steps in steroid synthesis, including the C11, C18, and C21 hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens, mediated through binding of Cytadren to cytochrome complexes.
Although Cytadren inhibits the synthesis of thyroxine by the thyroid gland, the compensatory increase in thyroid stimulating hormone (TSH) is frequently sufficient magnitude to overcome the inhibition of thyroid synthesis due to Cytadren. In spite of an increase of TSH, Cytadren has not been associated with increased prolactin secretion.
In this small study, the effect of aminoglutethimide on the disposition of estrogens in women with advanced breast cancer was investigated using bolus injections of 4-(14)C-estradiol and 6,7-(3)H-estrone sulfate, alone or in combination. No alterations in estrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-(14)C-estradiol clearance was not changed. (14)C-Estrone sulfate AUC was reduced by 43% at a low dose of aminoglutethimide (125 mg twice daily) and by 65% at a high dose (250 mg 4 times daily) with hydrocortisone acetate 25 mg twice daily. The estrone sulfate terminal elimination rate constant (lambda z) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens). A possible increase in estrone sulfate clearance during long term treatment was tested for by injecting 6,7-(3)H-estrone sulfate. These studies revealed a marked increase (mean 104%) in estrone sulfate clearance in patients receiving the high dose aminoglutethimide schedule. Following injection of 4-(14)C-estradiol plus 6,7-(3)H-estrone sulfate, the fraction of 4-(14)C-estradiol metabolized to estrone sulfate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of (14)C-estriol was observed after 4-(14)C-estradiol administration.
Aminoglutethimide (AMG), a potent inhibitor of steroidogenesis used in the treatment of breast cancer and some adrenal pathologies, abolished the induction of ornithine decarboxylase (ODC) elicited by peptide hormones and by dibutyryl-cAMP in steroidogenic tissues. This effect seems to be related to an inhibition of cAMP-dependent protein kinase (IC50 = 287 uM) rather than blockade of the steroidogenic pathway. This inhibition may explain some of the effects observed in AMG treatment which cannot be ascribed to its direct effect on the cytochrome P450scc complex or aromatase. Taking into account that ODC, the rate-limiting enzyme in polyamine synthesis, is elevated in many types of cancer and that overexpression of this enzyme is associated with cell transformation, one may speculate that the inhibitory action of AMG on protein kinase A represents a positive colateral effect of this drug in cancer therapy.

C13H16N2O2

232.28

232.121

125-84-8

2145

White to off-white solid powder

1.2±0.1 g/cm3

457.4±45.0 °C at 760 mmHg

152-154 °C(lit.)

230.4±28.7 °C

0.0±1.1 mmHg at 25°C

1.566

1.41

72.19

2

3

2

17

321

0

ROBVIMPUHSLWNV-UHFFFAOYSA-N

InChI=1S/C13H16N2O2/c1-2-13(8-7-11(16)15-12(13)17)9-3-5-10(14)6-4-9/h3-6H,2,7-8,14H2,1H3,(H,15,16,17)

3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione

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 (10.76 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 (10.76 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 (10.76 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: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 8 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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。