Farnesyl diphosphate synthase/FPPS

Alendronate is the most often prescribed medication among the bisphosphonates, which are frequently used to treat osteoporosis. The process of bone grinding, which impedes fracture healing, is strongly inhibited by bisphosphonates [2].

Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic techniques and their solubility in water and biological fluids was determined. An evaluation of the toxicity towards human healthy cells and also human breast, lung and bone (osteosarcoma) cell lines was performed. Globally, it was observed that the monoanionic OSILs showed lower toxicity than the corresponding dianionic structures to all cell types. The highest cytotoxic effect was observed in OSILs containing a [C2OHMIM] cation, in particular [C2OHMIM][ALN]. The latter showed an improvement in IC50 values of ca. three orders of magnitude for the lung and bone cancer cell lines as well as fibroblasts in comparison with ALN. The development of OSILs with high cytotoxicity effect towards the tested cancer cell types, and containing an anti-resorbing molecule such as ALN may represent a promising strategy for the development of new pharmacological tools to be used in those pathological conditions[1].

Absorption, Distribution and Excretion
Mean oral bioavailability of alendronic acid in women is 0.64% and in men is 0.59%. Bioavailability of alendronic acid decreases by up to 40% if it is taken within an hour of a meal.
Administration of radiolabeled alendronic acid results in 50% recovery in urine within 72 hours. No alendronic acid is recovered in the feces. Men excrete less alendronic acid than women, though race and advanced age do not affect elimination.
28L.
71mL/min.
Relative to an intravenous iv reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.
Alendronate sodium 70 mg oral solution and alendronate sodium 70 mg tablet are equally bioavailable.
A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast.
For more Absorption, Distribution and Excretion (Complete) data for Alendronic acid (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Urinary excretion is the sole method of elimination of alendronic acid and no metabolites are detected upon urine collection.
There is no evidence that alendronate is metabolized in animals or humans.
There is no evidence that alendronate is metabolized in humans or animals.
Route of Elimination: Following a single IV dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces.
Half Life: >10 years

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Biological Half-Life
Due to alendronic acid being incorporated into the skeleton, the terminal half life is estimated to be over 10 years.
The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate sodium (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Toxicity Summary
The action of Alendronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Alendronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited evidence indicates that breastfeeding after cessation of long-term bisphosphonate treatment appears to have no adverse effects on the infant. Because no information is available on the use of alendronate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of alendronate by a breastfed infant is unlikely. If the mother receives a bisphosphonate during pregnancy or nursing, some experts recommend monitoring the infant's serum calcium during the first 2 months postpartum.
◉ Effects in Breastfed Infants
Because alendronate can persist in the body for years after long-term administration, the following cases may be relevant. A woman received alendronate for 6 months, then pamidronate every 4 months for 1 year prior to conception. Her infant was breastfed (extent not stated) for 3 months. The infant had mild hypocalcemia at 2 months of age, but a normal calcium level and normal long bone development at 5 months of age.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
78%. Studies in rats show that plasma protein binding increases with decreasing alendronic acid plasma concentration and increasing pH.

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Interactions
Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).
It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of alendronate sodium. Therefore, patients must wait at least one-half hour after taking alendronate sodium before taking any other oral medications.
Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
For more Interactions (Complete) data for Alendronic acid (8 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 Density Conservation Agents
Alendronate sodium tablets are indicated for the treatment of osteoporosis, alendronate sodium tablets increases bone mass and reduce the incidence of fractures, including those of the hip and spine (vertebral compression fractures). Osteoporosis may be confirmed by the finding of low bone mass (for example, at least 2 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture. /Included in US product label/
Alendronate sodium tablets are indicated for the prevention of osteoporosis, alendronate sodium tablets may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture. /Included in US product label/
Alendronate sodium tablets are indicated for treatment to increase bone mass in men with osteoporosis. /Included in US product label/
For more Therapeutic Uses (Complete) data for Alendronic acid (7 total), please visit the HSDB record page.

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Drug Warnings
FDA notified healthcare professionals and patients about its ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer. There are insufficient data to recommend endoscopic screening of asymptomatic patients. FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.
Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass (for example, at least 1 standard deviation below the mean for healthy young adult women); thin body build; Caucasian or Asian race; and family history of osteoporosis. The presence of such risk factors may be important when considering the use of alendronate sodium tablets for prevention of osteoporosis.
/Alendronate sodium is contraindicated in the presence of/: Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes; hypersensitivity to any component of this product; hypocalcemia.
Alendronate sodium, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
For more Drug Warnings (Complete) data for Alendronic acid (18 total), please visit the HSDB record page.

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Pharmacodynamics
Alendronic acid tablets have a very low oral bioavialability. After administration it distributes into soft tissue and bone or is excreted in the urine. Alendronic acid does not undergo metabolism.

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

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)

Solubility in Formulation 1: 6.67 mg/mL (26.78 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)