Background and overview【1】
Alendronate is a third-generation bisphosphonate drug and is currently the first-line drug for the prevention and treatment of osteoporosis internationally. Studies have proven that regular use of the drug can significantly increase bone density and reduce the risk of local fractures. The main mechanism of action of alendronate is to bind to hydroxyapatite attached to the bone resorption surface, further increasing bone density by inhibiting osteoclast activity and promoting osteoclast apoptosis. However, the oral utilization rate of alendronate is low, with a study statistics of 0.7%, and it requires long-term medication. Patients have poor drug compliance and are at risk of gastrointestinal ulcers. The most important thing is that long-term use can cause systemic bone turnover. Excessive inhibition.
Osteoporosis is a disease that increases the risk of fractures. It is mainly characterized by reduced bone density, deterioration of bone microstructure, and changes in the amount and type of proteins in bones. The main harm of osteoporosis is that patients have an increased risk of fractures, which occur when normal people are not prone to fractures. This kind of fracture is also called a fragility fracture. Common locations include the spine, ribs, hips, wrists, etc. It is the main cause of disability or death in patients with osteoporosis. Statistics show that the incidence of osteoporosis is on the rise worldwide. There are more than 200 million osteoporosis patients in the world, and there are about 70 million osteoporosis patients in my country. Osteoporosis has become an important disease that harms human health, especially the health of middle-aged and elderly women. Bisphosphonates are a general term for a class of prescription drugs used to treat osteoporosis, including etidronate sodium, alendronate sodium, risedronate sodium, zoledronic acid, etc. Their chemical structures and pharmacological effects resemblance. Alendronate sodium, trade name Fosamax, is the most widely used anti-osteoporosis drug in the world. This product is a third-generation aminobisphosphonate bone resorption inhibitor with a strong affinity for intraosseous hydroxyapatite. , exerting an anti-bone resorption effect by inhibiting the activity of osteoclasts. Its anti-bone resorption effect is 1,000 times stronger than that of etidronate sodium, and it has no bone mineralization inhibition effect. Mainly used for osteoporosis in postmenopausal women, it can increase the bone mass of the spine, improve vertebral body distortion, height shortening, and fracture incidence (including hip bones, spine bones, and wrist bones).
Alendronate is the most widely used anti-osteoporosis drug in the world. It was launched in the United States in 1993. It can significantly increase patients’ bone density and reduce the risk of fractures. It is the first-line treatment for osteoporosis. Alendronate sodium is an aminobisphosphonate bone resorption inhibitor. It has a strong affinity with intraosseous hydroxyapatite and can enter the bone matrix hydroxyapatite crystals. When osteoclasts dissolve the crystals, the drug is released and can It inhibits the activity of osteoclasts and indirectly inhibits bone resorption through osteoblasts. It has the characteristics of strong anti-bone resorption activity and no inhibitory effect on bone mineralization. It is clinically used to treat osteoporosis in postmenopausal women and to prevent hip and spine fractures. It is important to note that all patients with osteoporosis should take calcium and vitamin D supplements if they cannot consume sufficient calcium and vitamin D from food. Alendronate sodium tablets, like all other aminobisphosphonates, may also cause local irritation to the upper gastrointestinal mucosa, so it should be used with caution in patients with active upper gastrointestinal diseases, such as dysphagia, esophageal disease, and gastritis. , duodenitis or ulcer patients.
Animal studies have shown that alendronate has the following mode of action. At the cellular level, alendronate has affinity for bone resorption sites, especially those where osteoclasts act. Under normal circumstances, osteoclasts adhere to the bone surface but the edges are not rough, and rough edges are a sign of active bone resorption. Alendronate does not affect osteoclast aggregation or adhesion, but it does inhibit osteoclast activity. Studies of the intraosseous site of action of radioactively labeled [3H]alendronate in mice have shown that uptake on the surface of osteoclasts is 10 times greater than on the surface of osteoblasts. After radioactively labeled [3H]alendronate was given to rats for 6 days and mice for 49 days, the bone tissue was examined and it was found that normal bone was formed on the surface of alendronate, which no longer formed after combining with the matrix. Pharmacologically active, alendronate must therefore be taken continuously to inhibit osteoclasts at newly formed resorptive surfaces. Histomorphometry in baboons and rats shows that alendronate reduces bone turnover (i.e., the number of bone remodeling sites) and that, at these remodeling sites, bone formation exceeds bone resorption, resulting in a progressive increase in bone mass.
Repeated dose-toxicity studies of one and three years in rats and dogs, respectively, found the following changes associated with alendronate: Retention of endogenous chondrogenic bone formation areas Initial cancellous bone; alkaline phosphatase activity continues to decrease; blood calcium and blood phosphorus concentrations transiently decrease. These are related to the expected pharmacological activities of alendronate. In species most sensitive to nephrotoxicity (e.g., dogs), nephrotoxicity occurs at doses equivalent to at least 100 mg in humans. Rats required higher doses to exhibit this nephrotoxicity. Gastrointestinal toxicity occurs only in rodents. This may be due to a direct effect on the mucosa and occurs only at doses above 2.5 mg/kg/day.
Using intravenous dosage as a reference, alendronate sodium 5-70 mg is given on an empty stomach and 2 hours before a standard breakfast. Its average oral bioavailability is 0.64% in women and 10 mg in men.mg is 0.6%, which is similar. Bioavailability is similarly reduced in both sexes (approximately 40%) if administered 1 or 1.5 hours before a standard breakfast. Osteoporosis research shows that this product is effective when given at least 30 minutes before the first meal or drink of the day.
Bioavailability is negligible if administered 2 hours or more after a standard breakfast. Taking alendronate sodium with coffee or orange juice can reduce its bioavailability by about 60%.
In healthy subjects, oral administration of prednisone (20 mg three times daily for 5 days) has no clinically significant effect on the oral bioavailability of alendronate (mean increase 20-44%).
Research shows that after intravenous administration of 1 mg/kg alendronate to rats, it is instantly distributed in soft tissues, but then rapidly redistributed in bone tissue or excreted in urine. Its average steady-state distribution volume in the human body, except for bone tissue, is at least 28L. Orally administered therapeutic doses of alendronate are difficult to analyze due to their low plasma concentration (less than 5ng/ml). Its plasma protein binding rate is approximately 78%.
After one-time intravenous administration of C14-labeled alendronate, it was found that about 50% of the radioactivity was excreted in the urine within 72 hours, and there was no or only a small amount of radioactivity in the feces. After a one-time intravenous administration of 10 mg of alendronate, the renal clearance rate was determined to be 71 ml/min, and the systemic clearance rate did not exceed 200 ml/min. Its plasma concentration drops by more than 95% within 6 hours after intravenous administration. Its terminal half-life in humans is estimated to be greater than 10 years, suggesting that alendronate is released from bone.
Preclinical studies have shown that this drug does not accumulate in bones and is quickly excreted in the urine. Long-term cumulative intravenous administration of 35 mg/kg in animals showed no evidence of saturation of bone resorption. Although clinical data are not available, renal clearance of alendronate is likely to be reduced when renal function is impaired, as shown in animal studies. Therefore, the accumulation of alendronate in the body may increase when kidney function is impaired.
Application
It is used medicinally to treat postmenopausal osteoporosis and senile osteoporosis, osteoporosis, ectopic ossification, such as Paget’s disease, osteitis deformans, kidney stones, malignant Hypercalcemia, etc.
Preparation
Gamma-aminobutyric acid (GABA), phosphorous acid, and phosphorus trichloride are used as raw materials, and diphenyl ether is used as the solvent to prepare alendronic acid, and then alendronate is prepared through alkalization. . The synthesis route is shown in the figure below:
Main references
[1] Yang Lin, Guo Ai, Ding Ye, YANG Lin, GU water-based amino resin O Ai, DING Ye- “Progress in Modern Biomedicine” 2007 Issue 7
