Farnesyl diphosphate synthase/FPPS

阿仑膦酸钠是双磷酸盐中最常用的处方药物，常用于治疗骨质疏松症。双膦酸盐强烈抑制阻碍骨折愈合的骨磨削过程[2]。

本文报道了根据阳离子类型，通过以下两种不同的可持续和直接的方法，从阿仑膦酸（ALN）定量合成八种新的单离子和二阴离子有机盐和离子液体（OSIL）。通过光谱技术对制备的ALN-OSIL进行了表征，并测定了它们在水和生物体液中的溶解度。对人类健康细胞以及人类乳腺、肺和骨（骨肉瘤）细胞系的毒性进行了评估。在全球范围内，观察到单阴离子OSIL对所有细胞类型的毒性均低于相应的二阴离子结构。在含有[C2OHMIM]阳离子的OSIL中观察到最高的细胞毒性作用，特别是[C2OHMI][ALN]。后者显示，与ALN相比，肺和骨癌症细胞系以及成纤维细胞的IC50值提高了约三个数量级。开发对测试的癌症细胞类型具有高细胞毒性效应的OSIL，并含有抗吸收分子（如ALN），这可能是开发用于这些病理条件的新药理学工具的一种有前景的策略[1]。

Absorption, Distribution and Excretion
The mean oral bioavailability of alendronate sodium is 0.64% in women and 0.59% in men. Bioavailability can be reduced by up to 40% when taken within one hour after a meal. Following administration of radiolabeled alendronate sodium, 50% is recovered in urine within 72 hours. Alendronate sodium is not detected in feces. Men excrete alendronate sodium less than women, but race and age do not affect excretion. 28 liters. 71 ml/min. The mean oral bioavailability of alendronate sodium is 0.64% in women when taken 5 to 70 mg two hours before a standard breakfast after an overnight fast, relative to the intravenous reference dose. The oral bioavailability (0.59%) of a 10 mg alendronate sodium tablet in men is similar to that in women when taken 2 hours before breakfast after an overnight fast.
The bioavailability of alendronate sodium 70 mg oral solution and alendronate sodium 70 mg tablets is the same.
One study investigated the effect of mealtime on the bioavailability of alendronate sodium in 49 postmenopausal women. Results showed that compared to taking it 2 hours before a meal, taking 10 mg alendronate sodium 0.5 hours or 1 hour before a standard breakfast reduced bioavailability by approximately 40%. In studies on the treatment and prevention of osteoporosis, alendronate sodium was effective when taken at least 30 minutes before breakfast.
The bioavailability of alendronate sodium is negligible whether taken with a standard breakfast or within two hours after breakfast.
For more complete data on the absorption, distribution, and excretion of alendronate (10 items in total), please visit the HSDB records page.
Metabolism/Metabolites
Urinary excretion is the only route of elimination of alendronate; no metabolites were detected in urine collection.
There is no evidence that alendronate sodium is metabolized in animals or humans.
There is no evidence that alendronate sodium is metabolized in humans or animals.
Elimination route: Following a single intravenous injection of [14C] alendronate sodium, approximately 50% of the radioactivity is excreted in the urine within 72 hours, with the remainder being excreted in small amounts or completely. No radioactive material was detected in feces.
Half-life: >10 years

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Biological half-life
Because alendronate is integrated into the bone, its terminal half-life is estimated to be over 10 years.
In humans, the terminal half-life is estimated to be over 10 years, which may reflect the release of alendronate sodium from the bone. Based on the above information, it is estimated that after 10 years of oral treatment with alendronate sodium (10 mg daily), the amount of alendronate sodium released daily from the bone is approximately 25% of the amount absorbed from the gastrointestinal tract.

Toxicity Summary
Alendronate sodium's effects on bone tissue are partly based on its affinity for hydroxyapatite, a component of the bone mineral matrix. Alendronate sodium also targets farnesyl pyrophosphate (FPP) synthase. Nitrogenous bisphosphonates (such as pamidronate sodium, alendronate sodium, risedronate sodium, ibandronate sodium, and zoledronic acid sodium) appear to act as lipid analogs of isoprene diphosphate, thereby inhibiting an enzyme in the mevalonate pathway—FPP synthase. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprene lipids (FPP and GGPP), which are crucial for the post-translational farnesylation and geranylation of small GTPase signaling proteins. This activity inhibits osteoclast activity and reduces bone resorption and bone turnover. In postmenopausal women, it reduces elevated bone turnover and, on average, results in a net increase in bone mass.

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Limited evidence suggests that discontinuing breastfeeding after long-term bisphosphonate treatment appears to have no adverse effects on the infant. Since there is currently no information on the use of alendronate sodium during lactation, alternative medications may be preferred, especially for breastfed newborns or premature infants. However, breastfed infants are unlikely to absorb alendronate sodium. If the mother takes bisphosphonates during pregnancy or lactation, some experts recommend monitoring the infant's serum calcium levels in the first two months postpartum.
◉ Effects on breastfed infants
Because alendronate sodium can persist in the body for several years after long-term use, the following may be relevant. A woman received alendronate sodium treatment for 6 months one year before conception, followed by pamidronate sodium treatment every 4 months thereafter. Her infant was breastfed for 3 months (the extent of breastfeeding was not specified). The infant presented with mild hypocalcemia at 2 months of age, but calcium levels were normal at 5 months of age, and long bone development was also normal.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
78%. Rat studies showed that plasma protein binding increased with decreasing plasma alendronate concentration and increasing pH.

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Interactions
Intravenous ranitidine doubled the bioavailability of oral alendronate sodium. The clinical significance of this increased bioavailability, and whether a similar increase would occur in patients taking oral H2 receptor antagonists, is currently unclear.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not cause a clinically significant change in the oral bioavailability of alendronate sodium (mean increase of 20% to 44%).
Calcium supplements, antacids, and certain oral medications may interfere with the absorption of alendronate sodium. Therefore, patients should wait at least half an hour after taking alendronate sodium before taking other oral medications. Taking alendronate sodium with coffee or orange juice reduces bioavailability by approximately 60%. For more complete data on drug interactions of alendronates (8 types in total), please visit the HSDB record page.

[1]. Teixeira S, et al. Alendronic Acid as Ionic Liquid: New Perspective on Osteosarcoma. Pharmaceutics. 2020 Mar 24;12(3). pii: E293.
[2]. Duckworth AD, et al. Effect of Alendronic Acid on Fracture Healing: A Multicenter Randomized Placebo-Controlled Trial. J Bone Miner Res. 2019 Jun;34(6):1025-1032.

Therapeutic Uses

Bone Mineral Degradation Protectant
Alendronate Sodium Tablets are indicated for the treatment of osteoporosis. Alendronate Sodium Tablets increase bone mass and reduce the incidence of fractures, including hip and spinal fractures (vertebral compression fractures). The diagnosis of osteoporosis is based on low bone mass (e.g., below the premenopausal mean by at least 2 standard deviations) or the presence or history of osteoporotic fractures. /US Product Label/
Alendronate Sodium Tablets are indicated for the prevention of osteoporosis. Alendronate Sodium Tablets may be considered for postmenopausal women at risk of osteoporosis who expect clinical efficacy in maintaining bone mass and reducing the risk of future fractures. /US Product Label/
Alendronate Sodium Tablets are indicated for the treatment of osteoporosis in men to increase bone mass. /Included in US Product Label/
For more complete data on the therapeutic uses of alendronate (7 types), please visit the HSDB record page.
Drug Warning
The FDA has notified healthcare professionals and patients that it is reviewing published research data to assess whether the use of oral bisphosphonates is associated with an increased risk of esophageal cancer. The FDA has not concluded that taking oral bisphosphonates increases the risk of esophageal cancer. There is currently insufficient data to recommend endoscopic screening for asymptomatic patients. The FDA will continue to evaluate all existing data supporting the safety and efficacy of bisphosphonates and will update the public as more information becomes available.
Bone loss is particularly rapid in postmenopausal women under the age of 60. Common risk factors associated with the development of postmenopausal osteoporosis include: early menopause; moderately low bone mass (e.g., at least one standard deviation below the mean for healthy young adult women); lean body type; Caucasian or Asian appearance; and a family history of osteoporosis. The presence of these risk factors may be important when considering the use of alendronate sodium tablets for osteoporosis prevention.
/Alendronate sodium is contraindicated in: esophageal abnormalities causing delayed esophageal emptying, such as esophageal stricture or achalasia; inability to stand or sit upright for at least 30 minutes; hypersensitivity to any component of this product; hypocalcemia.
As with other bisphosphonates, alendronate sodium may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse reactions, such as esophagitis, esophageal ulceration, and esophageal erosion, have been reported in patients treated with alendronate sodium, with occasional bleeding, and in rare cases, progression to esophageal stricture or perforation. In some cases, these adverse reactions are severe and require hospitalization. Therefore, physicians should be alert to any signs or symptoms that may indicate an esophageal reaction and should inform patients that alendronate sodium should be discontinued immediately and medical attention sought if dysphagia, dysphagia, retrosternal pain, or new or worsening heartburn occurs.
For more complete data on drug warnings for alendronate (18 in total), please visit the HSDB record page.

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Pharmacodynamics
The oral bioavailability of alendronate tablets is extremely low. After administration, the drug is distributed in soft tissues and bones, or excreted in the urine. Alendronate is not metabolized.

C4H13NO7P2

249.09612

249.017

C, 19.29; H, 5.26; N, 5.62; O, 44.96; P, 24.87

66376-36-1

Alendronate sodium hydrate;121268-17-5;Alendronic acid-d6;1035437-39-8;Alendronate sodium;129318-43-0; 66376-36-1 (free acid); 137504-90-6 (calcium); 138624-11-0 (free acid hydrate)

2088

Fine white powder

1.857 g/cm3

616.7ºC at 760 mmHg

230-235ºC

326.7ºC

-6.5

180.93

6

8

5

14

257

0

C(CC(O)(P(=O)(O)O)P(=O)(O)O)CN

OGSPWJRAVKPPFI-UHFFFAOYSA-N

InChI=1S/C4H13NO7P2/c5-3-1-2-4(6,13(7,8)9)14(10,11)12/h6H,1-3,5H2,(H2,7,8,9)(H2,10,11,12)

(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid

ALENDRONIC ACID; alendronate; 66376-36-1; Fosamax; (4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid; Acido alendronico; Acide alendronique; Acidum alendronicum;

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)

H2O : ~3.7 mg/mL (~14.85 mM)

配方 1 中的溶解度: 6.67 mg/mL (26.78 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。 (<60°C).

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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。