Tibolone   中文名称: 替勃龙

- Tibolone exerts biological effects by binding to sex hormone receptors, including estrogen receptors (ER) and progesterone receptors (PR)
- Tibolone modulates sexual behavior-related pathways by acting on central nervous system (CNS) sex hormone receptors (primarily estrogen receptors)

- 在种植体骨整合临床前体内模型（采用去卵巢[OVX]雌性SD大鼠，模拟绝经后骨质疏松状态）中：口服给予 替勃龙（Tibolone） 1 mg/kg/天，持续8周（钛种植体植入胫骨近端前4周+植入后4周），可显著增强骨整合。Micro-CT分析显示，替勃龙（Tibolone） 组的骨-种植体接触率（BIC）为51.2±6.3%，显著高于OVX对照组（29.5±5.4%，p<0.05）；此外，替勃龙（Tibolone） 组种植体周围骨体积分数（BV/TV）为0.42±0.05，较对照组（0.28±0.04）提高46.4%（p<0.05）。组织学检查进一步证实，替勃龙（Tibolone） 处理组种植体周围新骨形成增加，且无异常骨组织形态[1]
- 在雌性SD大鼠脊柱前凸（lordosis）行为研究中：去卵巢（OVX）大鼠每日皮下注射 替勃龙（Tibolone） 10 μg/只，连续7天。行为学测试（将大鼠与性活跃雄鼠共处10分钟）显示，替勃龙（Tibolone） 显著诱导lordosis行为：替勃龙（Tibolone） 组的lordosis评分（0~3分，3分为最大程度前凸）为2.9±0.2，显著高于OVX对照组（0.3±0.1，p<0.01）；替勃龙（Tibolone） 组的lordosis频率（雄鼠爬跨引发lordosis反应的百分比）为85.6±7.2%，对照组为12.3±4.5%（p<0.01）。值得注意的是，在停药后14天观察期内，替勃龙（Tibolone） 处理组未观察到lordosis行为的并发或序贯抑制现象[2]

- Protocol for implant osseointegration study: 48 female SD rats (8 weeks old, 220–250 g) were randomly divided into 4 groups (n = 12 per group): Sham-operated group (Sham), OVX control group, Tibolone -treated group (TIB), and Tibolone + alendronate + simvastatin combination group. Rats in the OVX, TIB, and combination groups underwent bilateral ovariectomy to induce postmenopausal osteoporosis; the Sham group underwent sham surgery (ovaries were exposed but not removed). Two weeks after surgery, the TIB group began receiving Tibolone (1 mg/kg/day) dissolved in 0.5% carboxymethyl cellulose (CMC) via oral gavage, once daily. Four weeks after the start of drug administration, all rats received a titanium implant (diameter 1.5 mm, length 5 mm) implanted into the proximal metaphysis of the right tibia under general anesthesia. Drug administration continued for another 4 weeks after implant placement. At the end of the 8-week treatment period, rats were euthanized; the right tibia with the implant was harvested for Micro-CT scanning, histological sectioning, and bone parameter analysis (BIC, BV/TV)[1]
- Protocol for lordosis behavior study: 30 female SD rats (10 weeks old, 230–260 g) were ovariectomized to eliminate endogenous sex hormone effects. Two weeks after OVX, rats were randomly divided into 2 groups (n = 15 per group): Tibolone -treated group and vehicle control group. The Tibolone group received subcutaneous injections of Tibolone (10 μg/rat) dissolved in sesame oil, once daily for 7 days. The control group received equal volumes of sesame oil. On the 7th day of drug administration, lordosis behavior was tested: each rat was placed in a transparent observation cage (40 × 30 × 25 cm) with a sexually experienced male rat (screened for consistent mounting behavior). The observer (blinded to group allocation) recorded the lordosis score (0 = no lordosis, 1 = partial lordosis, 2 = moderate lordosis, 3 = full lordosis) and lordosis frequency (number of lordosis responses divided by total male mounts × 100%) over a 10-minute period. Behavioral tests were repeated on days 1, 7, and 14 after drug withdrawal to assess sequential effects[2]

Absorption, Distribution and Excretion
Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug.
Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites in feces.
Elimination of tibolone is not dependent renal function.

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Metabolism / Metabolites
Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form.

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Biological Half-Life
The elimination half-life is approximately 45 h.

Hepatotoxicity
In large scale prospective studies, tibolone has been associated with a low rate of transient serum aminotransferase levels, being greater than 3 times the upper limit of normal in 0.9% of tibolone versus 0.2% of placebo recipients, but instances of clinically apparent acute liver injury were not reported. In Europe, where tibolone has been in clinical use, there have been isolated reports of clinically apparent liver injury arising 6 to 12 months after starting and associated with a hepatocellular pattern of serum enzyme elevations and jaundice. Reported cases were self-limited and resolved within 2 to 6 months of stopping. Immunoallergic features were not present nor were autoantibodies.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Protein Binding
Tibolone is 96% bound to plasma proteins, most likely albumin.

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- During the 8-week treatment period, rats in the Tibolone group showed no significant changes in body weight (weekly weight gain was comparable to the control group), no abnormal clinical signs (e.g., lethargy, diarrhea, hair loss), and no significant differences in serum alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), or creatinine levels compared to the Sham and OVX control groups, indicating no acute liver or kidney toxicity associated with Tibolone at the tested dose[1]
- No obvious toxic reactions (such as weight loss, abnormal activity, or organ damage) were observed in rats treated with Tibolone (10 μg/rat, subcutaneous injection) for 7 days. Serum biochemical tests (ALT, AST, BUN) performed at the end of the study showed no significant differences between the Tibolone group and the control group, suggesting no acute toxicity of Tibolone in this experimental setting. No drug-drug interaction or plasma protein binding data were reported[2]

[1]. Tibolone, alendronate, and simvastatin enhance implant osseointegration in a preclinical in vivo model. Clin Oral Implants Res. 2020 Jul;31(7):655-668.
[2]. Tibolone induces lordosis behavior, but not concurrent or sequential inhibition, in Sprague Dawley rats. Neurosci Lett. 2021 Apr 24;755:135916.

Pharmacodynamics
Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety.

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- Tibolone is a synthetic steroid with mixed estrogenic, progestogenic, and weak androgenic activities. In the context of implant osseointegration, its ability to enhance new bone formation around implants may be mediated by promoting osteoblast proliferation and differentiation, inhibiting osteoclast activity, and regulating bone metabolism-related cytokines (e.g., increasing osteoprotegerin [OPG] expression and decreasing receptor activator of nuclear factor-κB ligand [RANKL] expression), which is particularly relevant for improving implant stability in postmenopausal women with osteoporosis[1]
- Lordosis behavior is a female rodent sexual response regulated by central sex hormone signaling. The induction of lordosis by Tibolone in OVX rats suggests that it can substitute for endogenous estrogens to activate CNS pathways (e.g., the hypothalamic-pituitary-gonadal axis) involved in sexual behavior. The absence of concurrent or sequential inhibition indicates that Tibolone does not produce long-term suppressive effects on sexual behavior after short-term administration, which may have implications for its clinical use in managing sexual dysfunction associated with estrogen deficiency[2]

C21H28O2

312.44582

312.208

C, 80.73; H, 9.03; O, 10.24

5630-53-5

444008

White to off-white solid powder

1.1±0.1 g/cm3

447.4±45.0 °C at 760 mmHg

169 °C

190.6±21.3 °C

0.0±2.5 mmHg at 25°C

1.570

4.03

37.3

1

2

1

23

636

6

C#C[C@@]1(CC[C@H]2[C@@H]3[C@H](C)CC4=C(CCC(=O)C4)[C@H]3CC[C@@]21C)O

WZDGZWOAQTVYBX-JNHCMHTRSA-N

InChI=1S/C21H28O2/c1-4-21(23)10-8-18-19-13(2)11-14-12-15(22)5-6-16(14)17(19)7-9-20(18,21)3/h1,13,17-19,23H,5-12H2,2-3H3/t13-,17-,18+,19-,20+,21-/m1/s1

19-Norpregn-5(10)-en-20-yn-3-one, 17-hydroxy-7-methyl-, (7alpha,17alpha)-

Livial; Tinox; tibolone; 5630-53-5; Liviella; Livial; Org OD 14; Tibolona; Xyvion; Tibolonum; Tibofem Xyvion Tibolonum.

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。