Risedronate

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

log Kow = -0.29 /Estimated/

-3.6

Miscible in water. /Estimated/

1.04e+01 g/L

Hydroxyl radical reaction rate constant = 5.2X10-12 cu cm/molecule-sec at 25 °C /Estimated/

Fine, white to off-white crystalline powder; odorless; MW 305.09. Occurs as hemi-pentahydrate. Soluble in water. Essentially insoluble in common organic solvents. /Monosodium salt/

Soluble in aqueous solutions. /Sodium/

Danger

H290 (50%): May be corrosive to metals [Warning Corrosive to Metals]

P203, P234, P260, P261, P263, P264, P264+P265, P270, P271, P280, P301+P317, P301+P330+P331, P302+P352, P302+P361+P354, P304+P340, P305+P351+P338, P305+P354+P338, P316, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P363, P390, P403+P233, P405, P406, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl risedronate sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Risedronate Sodium/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Antacids or Mineral Supplements Containing Divalent Cations: Pharmacokinetic interaction (decrease risedronate absorption) when risedronate is used concomitantly with antacids or mineral supplements containing divalent cations (e.g. aluminum, calcium, magnesium). /Risedronate/

Nonsteroidal Anti-inflammatory Agents /(SRP: NSAIDs)/: No evidence of increased adverse upper GI effects. /Risedronate/

Histamine H2 Receptor Antagonists, Proton Pump Inhibitors: No evidence of increased adverse upper GI effects. /Risedronate/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,400(SRC), determined from a structure estimation method(2), indicates that anagrelide is expected to have slight mobility in soil(SRC). The pKa of the phosphoric acid moiety of risedronic acid is estimated to be about 2.8 based on the pKa of etidronic acid(3), an analogous compound containing a similar functional group. The estimated pKa indicates that this compound will primarily exist in the anionic form and anions do not volatilize from moist soil surfaces. Anagrelide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.8X10-10 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that risedronic acid is not expected to adsorb to suspended solids and sediment(SRC). The pKa of the phosphoric acid moiety of risedronic acid is estimated to be about 2.8 based on the pKa of etidronic acid(3), an analogous compound containing a similar functional group. The estimated pKa indicates that this compound will primarily exist as an anion in the environment and anions generally do not adsorb more strongly to organic carbon and clay than their neutral counterparts(4) and do not volatilize from water surfaces. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that are expected to hydrolyze under environmental conditions. According to a classification scheme(5), an estimated BCF of 3.2(SRC), from an estimated log Kow of -0.29(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), risedronic acid, which has an estimated vapor pressure of 2.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase risedronic acid may be removed from the air by wet and dry deposition(SRC). Risedronic acid does not contain chromophores that absorb light at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The action of risedronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Risedronate 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.

Side effects include abdominal pain, anxiety, back pain, belching, bladder irritation, bone disorders and pain, bronchitis, bursitis, cataracts, chest pain, colitis, constipation, depression, diarrhea, difficulty breathing, dizziness, dry eyes, eye infection, flu-like symptoms, gas, headache, high blood pressure, infection, insomnia, itching, joint disorders and pain, leg cramps, muscle pain, muscle weakness, nausea, neck pain, nerve pain, pain, pneumonia, rash, ringing in ears, sinus problems, sore throat, stomach bleeding, stuffy or runny nose, swelling, tendon problems, tumor, ulcers, urinary tract infection, vertigo, vision problems, and weakness.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for risedronic acid can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that risedronic acid is expected to have very high mobility in soil. The pKa of the phosphoric acid moiety of risedronic acid is estimated to be about 2.8 based on the pKa of etidronic acid(3), indicating that this compound will primarily exist in the dissociated form in the environment and anions generally do not adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

risedronate

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl risedronate sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Risedronate Sodium/

M05BA07

M - Musculo-skeletal system

QM - Musculo-skeletal system

Risedronatic acid binds to bone hydroxyapatite. Bone resorption causes local acidification, releasing risedronic acid which is that taken into osteoclasts by fluid-phase endocytosis. Endocytic vesicles are acidified, releasing risedronic acid to the cytosol of osteoclasts where they induce apoptosis through inhbition of farnesyl pyrophosphate synthase. Inhibition of osteoclasts results in decreased bone resorption.

Risedronate binds to bone hydroxyapatite and, at the cellular level, inhibits osteoclasts. Although the osteoclasts adhere normally to the bone surface, they show evidence of reduced active resorption (e.g., lack of ruffled border). Evidence from studies in rats and dogs indicates that risedronate treatment reduces bone turnover (activation frequency, i.e., the number of sites at which bone is remodeled) and bone resorption at remodeling sites. /Risedronate/

Risedronate sodium, a synthetic pyridinyl bisphosphonate analog of pyrophosphate, is an inhibitor of osteoclast-mediated bone resorption. / Risedronate sodium/

... 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. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system. /Risedronate/

The initial half life of risedronic acid is approximately 1.5 hours, with a terminal half life of 561 hours.

Initial: Approximately 1.5 hours; Terminal exponential: 480 hours (which may represent the dissociation of risedronate from the surface of bone). /Risedronate/

Risedronic acid is not likely not metabolized before elimination. The P-C-P group of bisphosphonates is resistant to chemical and enzymatic hydrolysis preventing metabolism of the molecule.

There is no evidence that risedronate is metabolized in humans or animals. /Risedronate/

No evidence found for metabolization of risedronate in humans or mammals. Route of Elimination: Risedronate is excreted unchanged primarily via the kidney. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Half Life: 1.5 hours

KM2Z91756Z

RISEDRONIC ACID

Established Pharmacologic Class [EPC] - Bisphosphonate

Chemical Structure [CS] - Diphosphonates

Risedronic acid is a Bisphosphonate.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Agents that inhibit BONE RESORPTION and/or favor BONE MINERALIZATION and BONE REGENERATION. They are used to heal BONE FRACTURES and to treat METABOLIC BONE DISEASES such as OSTEOPOROSIS.

Oral bioavailability is 0.63% and maximum absorption is approximately 1 hour after dosing. Administration half and hour before a meal reduces bioavailability by 55% compared to fasting and dosing 1 hour before a meal reduces bioavailability by 30%.

Risedronate is excreted by the kidneys and the unabsorbed dose is eliminated in the feces.

13.8 L/kg.

Mean renal clearance was 52mL/min and mean total clearance was 73mL/min.

/Absorption is/ rapid and independent of dose, occurring throughout the upper gastrointestinal tract. Mean oral bioavailability is 0.63% and is decreased when administered with food. Administration either 0.5 hour before breakfast or 2 hours after dinner reduces the extent of absorption by 55% compared to the fasting state (no food or drink for 10 hours before or 4 hours after administration). Administration 1 hour before breakfast reduces the extent of absorption by 30% compared with the fasting state. /Risedronate/

Studies in rats and dogs with intravenously administered single doses of radiolabeled risedronate showed that approximately 60% of the dose was distributed to bone. The mean steady-state volume of distribution is 6.3 L/kg of body weight in humans. /Risedronate/

MEDICATION: Bone resorption inhibitor.

Use (kg; approx.) in Germany (2009): >100

For the treatment of Paget's disease of the bone (osteitis deformans), postmenopausal and glucocorticoid-induced osteoporosis

Bisphosphonate antiresorptive agent.

Information available in 2005 indicated that Risedronate sodium was used in the manufacture of pharmaceutical preparations in the following countries: Algeria, Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Czech Republic, Dominican Republic, Ecuador, El Salvador, Finland, France, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, Indonesia, Ireland, Israel, Italy, Japan, Netherlands, Nicaragua, Norway, Panama, Poland, Portugal, Romania, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, United States (1,2) /Risedronate Sodium/