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Identification
NameAlendronate
Accession NumberDB00630  (APRD00561)
Typesmall molecule
Groupsapproved
Description

Alendronate is a nitrogen-containing, second generation bisphosphonate. Bisphosphonates were first used to treat Paget’s disease in 1971. This class of medications is comprised of inorganic pyrophosphate analogues that contain non-hydrolyzable P-C-P bonds. Similar to other bisphosphonates, alendronate has a high affinity for bone mineral and is taken up during osteoclast resorption. Alendronate inhibits farnesyl pyrophosphate synthetase, one of the enzymes in the mevalonic acid pathway involved in producing isoprenoid compounds that are essential for post-translational modification of small guanosine triphosphate (GTP)-binding proteins, such as Rho, Ras and Rab. Inhibition of this process interferes with osteoclast function and survival. Alendronate is used for the treatment of osteoporosis and Paget’s disease.

Structure
Thumb
Synonyms
SynonymLanguageCode
Acide AlendroniqueFrenchINN
Acido AlendronicoSpanishINN
Acidum AlendronicumLatinINN
Alendronic acidNot AvailableINN
Salts
Name/CAS Structure Properties
Alendronate Sodium
121268-17-5
Thumb
  • InChI Key: DCSBSVSZJRSITC-UHFFFAOYNA-M
  • Monoisotopic Mass: 325.0303635
  • Average Mass: 325.1237
DBSALT000315
Brand names
NameCompany
AlenotopPliva
AlnedLaboratorios Belmac
ArendalIvax
BeenosGedeon Richter
BerlexDuncan
BinostoNot Available
DenfosBiofarma
DensidronMepha
DronatFarmavita
DurostPerumed
FixopanGrupo Farma
ForosaKemofarmacija
FosagenAspen Pharmacare
FosalenTeriak
FosamaxMerck
FosminHospimedikka
FostolinActavis
FosvalSaval
HuesoboneFarmaceutica Latina
LendrateActavis
OseolenIntipharma
OstemaxPolpharma
Brand mixtures
Brand NameIngredients
Fosamax PlusAlendronic Acid and Colecalciferol
Fosavancealendronate sodium + cholecalciferol
Categories
CAS number66376-36-1
WeightAverage: 249.096
Monoisotopic: 249.016724799
Chemical FormulaC4H13NO7P2
InChI KeyOGSPWJRAVKPPFI-UHFFFAOYSA-N
InChI
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)
IUPAC Name
(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid
SMILES
NCCCC(O)(P(O)(O)=O)P(O)(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganophosphorus Compounds
ClassOrganic Phosphonic Acids and Derivatives
SubclassOrganic Phosphonic Acids
Direct parentOrganic Phosphonic Acids
Alternative parentsPolyamines; Monoalkylamines
Substituentspolyamine; primary amine; primary aliphatic amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the organic phosphonic acids. These are organic compounds containing phosphonic acid.
Pharmacology
IndicationFor the treatment and prevention of osteoporosis in women and Paget's disease of bone in both men and women.
PharmacodynamicsAlendronate, a second-generation bisphosphonate is the first member of a group of drugs which strengthens bone. Alendronate is used to reduce hypercalcemia in tumor-induced bone disease, to treat corticosteroid-induced osteoporosis and Paget's disease, and to prevent osteoporosis in postmenopausal women.
Mechanism of actionThe 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.
AbsorptionRelative to an intravenous (IV) reference dose, the mean oral bioavailability of alendronate in women was 0.7% for doses ranging from 5 to 40 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 (0.78%) when administered after an overnight fast and 2 hours before breakfast.
Volume of distribution
  • 28 L
Protein binding78%
Metabolism

There is no evidence that alendronate is metabolized in humans or animals.

Route of eliminationFollowing 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
Clearance
  • <200 mL/min [A single 10 mg IV dose]
ToxicityAlendronate can damage the esophagus both by toxicity from the medication itself and by nonspecific irritation secondary to contact between the pill and the esophageal mucosa, similar to other cases of "pill esophagitis."
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.9554
Blood Brain Barrier + 0.7065
Caco-2 permeable - 0.7079
P-glycoprotein substrate Non-substrate 0.6606
P-glycoprotein inhibitor I Non-inhibitor 0.947
P-glycoprotein inhibitor II Non-inhibitor 0.9894
Renal organic cation transporter Non-inhibitor 0.9205
CYP450 2C9 substrate Non-substrate 0.8536
CYP450 2D6 substrate Non-substrate 0.7997
CYP450 3A4 substrate Non-substrate 0.6792
CYP450 1A2 substrate Non-inhibitor 0.7567
CYP450 2C9 substrate Non-inhibitor 0.9089
CYP450 2D6 substrate Non-inhibitor 0.9344
CYP450 2C19 substrate Non-inhibitor 0.9091
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9914
Ames test Non AMES toxic 0.7079
Carcinogenicity Non-carcinogens 0.7783
Biodegradation Ready biodegradable 0.6547
Rat acute toxicity 1.6956 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8571
hERG inhibition (predictor II) Non-inhibitor 0.8929
Pharmacoeconomics
Manufacturers
  • Merck and co inc
  • Apotex inc
  • Aurobindo pharma ltd
  • Austarpharma llc
  • Barr laboratories inc
  • Cadista pharmaceuticals inc
  • Dr reddys laboratories ltd
  • Genpharm ulc
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Sun pharma global inc
  • Teva pharmaceuticals usa
  • Watson laboratories
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
SolutionOral70 mg/75 ml
TabletOral10 mg
TabletOral35 mg
TabletOral40 mg
TabletOral5 mg
TabletOral70 mg
Prices
Unit descriptionCostUnit
Fosamax Plus D 4 70-2800 mg-Unit tablet Disp Pack107.66USDdisp
Fosamax Plus D 4 70-5600 mg-Unit tablet Disp Pack107.66USDdisp
Fosamax 1 Package = 4 tablet (70 mg) Package101.96USDpackage
Fosamax 1 Package = 4 tablet (35 mg) Package97.2USDpackage
Alendronate Sodium 4 35 mg tablet Package85.23USDpackage
Alendronate Sodium 4 70 mg tablet Package85.23USDpackage
Fosamax 70 mg/75ml Solution 75ml Bottle34.75USDbottle
Fosamax plus d 70 mg-5600 iu25.88USDeach
Fosamax 70 mg tablet24.51USDtablet
Fosamax 35 mg tablet23.36USDtablet
Fosamax plus d 70 mg-2800 iu21.85USDeach
Alendronate sodium 35 mg tablet20.49USDtablet
Alendronate sodium 70 mg tablet20.49USDtablet
Fosamax 40 mg tablet7.52USDtablet
Alendronate sodium 40 mg tablet6.73USDtablet
Fosamax 5 mg tablet3.4USDtablet
Fosamax 10 mg tablet3.4USDtablet
Alendronate sodium 10 mg tablet2.99USDtablet
Alendronate sodium 5 mg tablet2.99USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States59943291999-01-172019-01-17
United States53589411992-12-022012-12-02
Canada21901482006-02-142015-05-12
Canada22945952001-08-212018-07-17
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point234 dec °CPhysProp
water solubility1mg/LNot Available
logP-4.3Not Available
pKa2.72 (at 25 °C)MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
water solubility1.69e+01 g/lALOGPS
logP-1.3ALOGPS
logP-4.2ChemAxon
logS-1.2ALOGPS
pKa (strongest acidic)0.69ChemAxon
pKa (strongest basic)9.91ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count8ChemAxon
hydrogen donor count6ChemAxon
polar surface area161.31ChemAxon
rotatable bond count5ChemAxon
refractivity47.37ChemAxon
polarizability19.4ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraMS/MS
References
Synthesis Reference

Masahiko Dohi, Yuji Makino, Takao Hujii, “Sodium alendronate preparation for local administration.” U.S. Patent US5958908, issued September, 1997.

US5958908
General Reference
  1. Russell RG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008 Jun;19(6):733-59. Pubmed
External Links
ResourceLink
KEGG CompoundC07752
PubChem Compound2088
PubChem Substance46507199
ChemSpider2004
BindingDB25313
ChEBI2567
ChEMBLCHEMBL870
Therapeutic Targets DatabaseDAP000182
PharmGKBPA448082
HETAHD
Drug Product Database2261715
RxListhttp://www.rxlist.com/cgi/generic/alendron.htm
Drugs.comhttp://www.drugs.com/cdi/alendronate.html
WikipediaAlendronate
ATC CodesM05BA04
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelshow(105 KB)
MSDSshow(24.7 KB)
Interactions
Drug Interactions
Drug
CalciumFormation of non-absorbable complexes
Calcium AcetateCalcium Salts may decrease the serum concentration of Bisphosphonate Derivatives such as alendronate. Avoid administration of oral calcium supplements within 30 minutes after alendronate.
Calcium ChlorideCalcium salts may decrease the serum concentration of bisphosphonate derivatives. Avoid administration of oral calcium supplements within 30 minutes after alendronate/risedronate.
DiclofenacIncreased risk of gastric toxicity
DiflunisalIncreased risk of gastric toxicity
EtodolacIncreased risk of gastric toxicity
FenoprofenIncreased risk of gastric toxicity
FlurbiprofenIncreased risk of gastric toxicity
IbuprofenIncreased risk of gastric toxicity
IndomethacinIncreased risk of gastric toxicity
Iron DextranFormation of non-absorbable complexes
KetorolacIncreased risk of gasrtic toxicity
MagnesiumFormation of non-absorbable complexes
Mefenamic acidIncreased risk of gastric toxicity
NabumetoneIncreased risk of gastric toxicity
NaproxenIncreased risk of gastric toxicity
OxaprozinIncreased risk of gastric toxicity
OxyphenbutazoneIncreased risk of gastric toxicity
PiroxicamIncreased risk of gastric toxicity
TenoxicamIncreased risk of gastric toxicity
Food Interactions
  • Take 30-60 minutes before breakfast.
  • Take with a full glass of water.

Targets

1. Farnesyl pyrophosphate synthase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Farnesyl pyrophosphate synthase P14324 Details

References:

  1. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000 Jan 1;373(1):231-41. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42. Pubmed
  4. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. Pubmed

2. Hydroxylapatite

Kind: small molecule

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details

References:

  1. Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. Pubmed
  2. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006 May;38(5):617-27. Epub 2005 Jul 20. Pubmed

3. Tyrosine-protein phosphatase non-receptor type 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein phosphatase non-receptor type 4 P29074 Details

References:

  1. Opas EE, Rutledge SJ, Golub E, Stern A, Zimolo Z, Rodan GA, Schmidt A: Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Biochem Pharmacol. 1997 Sep 15;54(6):721-7. Pubmed

4. Receptor-type tyrosine-protein phosphatase S

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Receptor-type tyrosine-protein phosphatase S Q13332 Details

References:

  1. Opas EE, Rutledge SJ, Golub E, Stern A, Zimolo Z, Rodan GA, Schmidt A: Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Biochem Pharmacol. 1997 Sep 15;54(6):721-7. Pubmed
  2. Schmidt A, Rutledge SJ, Endo N, Opas EE, Tanaka H, Wesolowski G, Leu CT, Huang Z, Ramachandaran C, Rodan SB, Rodan GA: Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3068-73. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

5. Receptor-type tyrosine-protein phosphatase epsilon

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Receptor-type tyrosine-protein phosphatase epsilon P23469 Details

References:

  1. Schmidt A, Rutledge SJ, Endo N, Opas EE, Tanaka H, Wesolowski G, Leu CT, Huang Z, Ramachandaran C, Rodan SB, Rodan GA: Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3068-73. Pubmed

6. V-type proton ATPase catalytic subunit A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
V-type proton ATPase catalytic subunit A P38606 Details

References:

  1. David P, Nguyen H, Barbier A, Baron R: The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H(+)-ATPase. J Bone Miner Res. 1996 Oct;11(10):1498-507. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on January 17, 2014 12:57