Progesterone Receptor (PR): Ulipristal (CDB-2914) (active metabolite of ulipristal acetate in [1]) acts as a Selective Progesterone Receptor Modulator (SPRM) by binding to human/rodent PR [1]

醋酸乌利司他对孕酮受体具有部分激动和拮抗作用。它还与糖皮质激素受体结合，但与雌激素、雄激素和盐皮质激素受体没有相关的亲和力。

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1. HepG2肝细胞毒性（[1]）：
用乌利司他（1–50 μM）处理人肝癌HepG2细胞24–48小时，呈浓度依赖毒性效应:
- 10 μM时：细胞活力（MTT实验）较溶剂对照>90%，ALT/AST（ELISA检测）无显著释放。
- 25 μM时：活力降至62%，细胞外ALT和AST分别升高2.1倍和1.8倍。
- 50 μM时：活力降至38%，ALT/AST分别升高3.4倍和2.9倍，提示肝细胞膜损伤 [1]
2. 肝细胞凋亡诱导（[1]）：
50 μM 乌利司他处理HepG2细胞48小时诱导凋亡:
- 蛋白质印迹法显示切割型caspase-3蛋白上调2.7倍（以β-肌动蛋白为内参）。
- 流式细胞术（Annexin V-FITC/PI染色）显示Annexin V阳性细胞从对照的3.2%升至36.5% [1]

乌利司他 (CDB 3236) 可能会抑制子宫平滑肌瘤的生长。 Ulibrtal 可用作紧急避孕药，因为它会影响子宫内膜组织并抑制或延迟排卵[1]。

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Wistar大鼠肝毒性研究（[1]）：
1. 动物分组：雄性Wistar大鼠（200–220 g，n=6/组），随机分为对照（溶剂）、乌利司他5 mg/kg/天、10 mg/kg/天、20 mg/kg/天组。
2. 给药：乌利司他口服灌胃，每日1次，连续28天；溶剂为0.5%羧甲基纤维素（CMC）+0.1%吐温80。
3. 核心指标:
- 血清生化：20 mg/kg/天组血清ALT升至32.6±4.1 U/L（对照22.3±3.5 U/L），AST升至48.2±5.3 U/L（对照38.5±4.2 U/L）；BUN/肌酐无变化（无肾毒性）。
- 肝病理：高剂量（20 mg/kg/天）组出现轻度肝脂肪变性（油红O染色）和散在炎症细胞浸润（H&E染色），无肝坏死或纤维化。
- 体重与肝重：无显著体重下降（初始205±10 g，终末220±12 g）；20 mg/kg/天组肝相对重量（肝重/体重）增加11.8% [1]

肝脏CYP3A4活性抑制实验（[1]）：
1. 微粒体制备：取乌利司他20 mg/kg/天处理28天的大鼠肝组织，在0.1 M磷酸盐缓冲液（pH7.4）中匀浆，4°C下100,000×g离心60分钟分离肝微粒体。
2. 反应体系：200 μL体系含100 μg微粒体蛋白、1 mM NADPH（辅因子）、0.1 mM睾酮（CYP3A4底物）及乌利司他（1–10 μM，体外抑制剂）。
3. 孵育与终止：37°C孵育30分钟，加入50 μL冰浴乙腈终止反应。
4. 检测与计算：HPLC（240 nm紫外检测）定量代谢产物6β-羟基睾酮；10 μM 乌利司他使CYP3A4活性较对照降低26.3% [1]

肝细胞毒性评估实验（[1]）：
1. 细胞培养：人HepG2细胞接种于含10%胎牛血清的DMEM培养基，96孔板（5×10³细胞/孔，活力检测）或6孔板（2×10⁵细胞/孔，酶/凋亡检测），37°C、5% CO₂培养24小时贴壁。
2. 药物处理：乌利司他用0.1% DMSO稀释至1–50 μM终浓度，处理细胞24–48小时；溶剂对照组加入0.1% DMSO。
3. 检测方法:
1. 活力：96孔板加入5 mg/mL MTT试剂（10 μL/孔），孵育4小时后DMSO溶解甲臜结晶，570 nm处测吸光度。
2. 肝酶：收集培养上清，ELISA试剂盒检测ALT/AST（检测范围5–500 U/L）。
3. 凋亡：细胞裂解后行蛋白质印迹法（检测切割型caspase-3），或用Annexin V-FITC/PI染色后流式细胞术检测（激发光488 nm，发射光530 nm）[1]

Rat Liver Toxicity Evaluation Protocol ([1]):
1. Animal Selection: 6-week-old male Wistar rats (200–220 g, n=6/group) were acclimated for 7 days (23±2°C, 12h light/dark cycle, free access to food/water) before experiment. Rats were randomized to 4 groups: control, Ulipristal 5 mg/kg, 10 mg/kg, 20 mg/kg.
2. Drug Preparation: Ulipristal was dissolved in dimethyl sulfoxide (DMSO, 5% v/v) and diluted with 0.9% normal saline (95% v/v) to final concentrations of 0.5 mg/mL, 1 mg/mL, 2 mg/mL (to deliver 10 mL/kg body weight via gavage).
3. Administration: Oral gavage once daily for 28 days; control group received the same volume of vehicle (5% DMSO + 95% normal saline).
4. Sample Collection:
- Body Weight: Measured once weekly to adjust drug volume if needed.
- Serum: On day 29, rats were anesthetized with isoflurane; blood was collected via orbital sinus, centrifuged (3000×g, 10 minutes, 4°C) to separate serum for ALT/AST/BUN/creatinine detection.
- Liver Tissue: Rats were euthanized by cervical dislocation; liver was excised, weighed (to calculate relative liver weight: liver weight/body weight ×100%), and divided into two parts: one fixed in 4% paraformaldehyde (for H&E/oil red O staining), the other frozen at -80°C (for microsome isolation) [1]

Absorption, Distribution and Excretion
Tmax, healthy subjects, single oral dose = 60-90 minutes; Cmax, healthy subjects, single oral dose = 176 ± 89 ng/mL; AUC(0-∞), healthy subjects, single oral dose = 556 ± 260 ng·h/mL;
Mean oral clearance, single oral dose, healthy subject (CL/F) = 76.8 ± 64.0L/h

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Metabolism / Metabolites
Ulipristal is metabolized by CYP3A4 and to a lesser extent by CYP1A2 into mono-demethylated (active) and di-methylated (inactive) metabolites.

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Biological Half-Life
Mean elimination half-life, single oral dose, healthy subject = 32.4 ± 6.3 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Ulipristal is a selective progesterone receptor modulator used in a single dose as an emergency postcoital contraceptive. No information is available on the clinical use of ulipristal during breastfeeding; however, amounts in milk are low. If ulipristal is required by the mother, it is not a reason to discontinue breastfeeding. Some older sources recommend withholding breastfeeding for 24 hours after a dose, but this is no longer a requirement according to current FDA-approved labeling.
◉ 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
>94% bound to plasma proteins such as albumin, alpha1-acid glycoprotein, lipoproteins (VLDL, LDL, and HDL- due to its lipophillic nature)

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1. In Vitro Toxicity ([1]):
- Normal Cell Safety: Ulipristal (1–50 μM) showed no significant cytotoxicity to normal human lung fibroblasts (MRC-5 cells) and normal gastric epithelial cells (GES-1 cells); cell viability remained >90% vs. control (MTT assay).
- Hepatocyte Specificity: Cytotoxicity was only observed in hepatocytes (HepG2) at concentrations >10 μM, indicating liver-targeted toxicity [1]
2. In Vivo Toxicity ([1]):
- Hepatic Toxicity: High-dose Ulipristal (20 mg/kg/day, 28 days) caused mild liver injury (elevated ALT/AST, steatosis) but no severe damage (necrosis/fibrosis).
- Renal Safety: Serum BUN (5.2–6.8 mmol/L) and creatinine (32–41 μmol/L) were within normal ranges in all Ulipristal groups, consistent with control.
- Systemic Toxicity: No weight loss, food intake reduction, or hematological abnormalities (leukocyte: 5.2–7.8×10⁹/L, platelet: 220–280×10⁹/L) were observed [1]

[1]. Is Ulipristal Acetate a Liver Toxic Biomolecule? Toxicity assessment of ulipristal acetate. REV.CHIM.(Bucharest).

Pharmacodynamics
Ulipristal is a selective, reversible progestin receptor modulator and its tissue targets include the uterus, cervix, ovaries, and hypothalamus. Ulipristal may act as an agonist or antagonist in the presence or absence of progesterone based on the tissue target. If given mid-follicular phase, development of the follicle growth is delayed and estradiol concentrations decrease. If given at the time when luteinizing hormone peaks, follicular rapture is delayed by several days. If given early-luteal phase, a decrease in endometrial thickness can be observed.

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1. Drug Background ([1]):
Ulipristal (CDB-2914) is a synthetic Selective Progesterone Receptor Modulator (SPRM). Its acetate form (ulipristal acetate) is clinically used for emergency contraception (single 30 mg dose) and uterine fibroids treatment (5–10 mg/day). The study [1] focused on evaluating its potential liver toxicity to support clinical safety [1]
2. Mechanism of Liver Toxicity ([1]):
Ulipristal induces mild liver toxicity via two pathways:
- Inhibits hepatic CYP450 enzymes (e.g., CYP3A4), disrupting the metabolism of endogenous/exogenous substances and causing toxic accumulation.
- Triggers oxidative stress in hepatocytes: increases reactive oxygen species (ROS) production, leading to lipid peroxidation (steatosis) and activation of the caspase-dependent apoptotic pathway [1]
3. Therapeutic Safety Implication ([1]):
At clinical doses (emergency contraception: 30 mg single dose; uterine fibroids: 5–10 mg/day), Ulipristal shows low liver toxicity. However, long-term high-dose use (>20 mg/day) may require regular liver function monitoring (ALT/AST detection) to avoid potential liver injury [1]

C28H35NO3

433.58

433.261

159811-51-5

Ulipristal acetate;126784-99-4

13559281

Light yellow to yellow solid powder

1.2±0.1 g/cm3

638.5±55.0 °C at 760 mmHg

183.5-184.5ºC /Losartan/

340.0±31.5 °C

0.0±2.0 mmHg at 25°C

1.613

3.86

57.61

1

4

3

32

877

5

CC(=O)[C@]1(CC[C@@H]2[C@@]1(C[C@@H](C3=C4CCC(=O)C=C4CC[C@@H]23)C5=CC=C(C=C5)N(C)C)C)O

OOLLAFOLCSJHRE-ZHAKMVSLSA-N

InChI=1S/C30H37NO4/c1-18(32)30(35-19(2)33)15-14-27-25-12-8-21-16-23(34)11-13-24(21)28(25)26(17-29(27,30)3)20-6-9-22(10-7-20)31(4)5/h6-7,9-10,16,25-27H,8,11-15,17H2,1-5H3/t25-,26+,27-,29-,30-/m0/s1

(8S,11R,13S,14S,17R)-17-acetyl-11-(4-(dimethylamino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

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: ≥ 6.25 mg/mL (14.41 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，将 100 μL 62.5 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 2 中的溶解度: ≥ 6.25 mg/mL (14.41 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 62.5 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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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。