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Identification
NameAlfacalcidol
Accession NumberDB01436
TypeSmall Molecule
GroupsApproved, Nutraceutical
Description

Alfacalcidol is an active metabolite of Vitamin D, which performs important functions in regulation of the calcium balance and the bone metabolism. Alfacalcidol is Vitamin D-hormone analog which is activated by the enzyme 25-hydroxylase in the liver for systemic and in osteoblasts for local D-hormone actions. It possesses a unique pattern of pleiotropic effects on, e.g. gut, bone, pararthyroids, muscle and brain. Alfacalcidol is superior to plain vitamin D (cholecalciferol) because the final kidney activation of the latter is regulated by a negative feedback mechanism. (PMID:17438884,17668216)

Structure
Thumb
Synonyms
SynonymLanguageCode
(5Z,7e)-9,10-Seco-5,7,10(19)-cholestatrien-1alpha,3beta-diolNot AvailableNot Available
1-hydroxycholecalciferolNot AvailableNot Available
1alpha-Hydroxy-vitamin D3Not AvailableNot Available
1alpha-hydroxycholecalciferolNot AvailableNot Available
1alpha-hydroxyvitamin D3Not AvailableNot Available
9,10-Secocholesta-5,7,10(19)-triene-1alpha,3beta-diolNot AvailableNot Available
AlfacalcidolumNot AvailableNot Available
AlsiodolNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AlsiodolNot Available
One AlphaNot Available
Brand mixturesNot Available
Categories
CAS number41294-56-8
WeightAverage: 400.6371
Monoisotopic: 400.334130652
Chemical FormulaC27H44O2
InChI KeyOFHCOWSQAMBJIW-AVJTYSNKSA-N
InChI
InChI=1S/C27H44O2/c1-18(2)8-6-9-19(3)24-13-14-25-21(10-7-15-27(24,25)5)11-12-22-16-23(28)17-26(29)20(22)4/h11-12,18-19,23-26,28-29H,4,6-10,13-17H2,1-3,5H3/b21-11+,22-12-/t19-,23-,24-,25+,26+,27-/m1/s1
IUPAC Name
(1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-7a-methyl-1-[(2R)-6-methylheptan-2-yl]-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol
SMILES
CC(C)CCC[C@@H](C)[C@@]1([H])CC[C@@]2([H])\C(CCC[C@]12C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassVitamin D and Derivatives
Direct parentVitamin D and Derivatives
Alternative parentsSesterterpenes; Cyclohexanols; Cyclic Alcohols and Derivatives; Polyamines
Substituentscyclohexanol; cyclic alcohol; secondary alcohol; polyamine; alcohol
Classification descriptionThis compound belongs to the vitamin d and derivatives. These are compounds containing a secosteroid backbone, usually secoergostane or secocholestane.
Pharmacology
IndicationAlfacalcidol is an active metabolite of Vitamin D, which performs important functions in regulation of the calcium balance and the bone metabolism.
PharmacodynamicsAlfacalcidol is Vitamin D-hormone analog which is activated by the enzyme 25-hydroxylase in the liver for systemic and in osteoblasts for local D-hormone actions.
Mechanism of actionThe first step involved in the activation of vitamin D3 is a 25-hydroxylation which is catalysed by the 25-hydroxylase in the liver and then by other enzymes. The mitochondrial sterol 27-hydroxylase catalyses the first reaction in the oxidation of the side chain of sterol intermediates. The active form of vitamin D3 (calcitriol) binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription. Calcitriol increases the serum calcium concentrations by: increasing GI absorption of phosphorus and calcium, increasing osteoclastic resorption, and increasing distal renal tubular reabsorption of calcium. Calcitriol appears to promote intestinal absorption of calcium through binding to the vitamin D receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityHypercalcemia - Early symptoms of hypercalcemia, include nausea and vomiting, weakness, headache, somnolence, dry mouth, constipation, metallic taste, muscle pain and bone pain. Late symptoms and signs of hypercalcemia, include polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, pancreatitis, photophobia, rhinorrhea, pruritis, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated ALT (SGPT) and AST (SGOT), ectopic calcification, nephrocalcinosis, hypertension and cardiac arrhythmias.
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 + 0.9865
Blood Brain Barrier + 0.9142
Caco-2 permeable + 0.7866
P-glycoprotein substrate Substrate 0.7469
P-glycoprotein inhibitor I Non-inhibitor 0.5785
P-glycoprotein inhibitor II Inhibitor 0.5574
Renal organic cation transporter Non-inhibitor 0.7945
CYP450 2C9 substrate Non-substrate 0.8188
CYP450 2D6 substrate Non-substrate 0.8945
CYP450 3A4 substrate Substrate 0.7656
CYP450 1A2 substrate Non-inhibitor 0.8249
CYP450 2C9 substrate Non-inhibitor 0.8802
CYP450 2D6 substrate Non-inhibitor 0.9434
CYP450 2C19 substrate Non-inhibitor 0.7466
CYP450 3A4 substrate Non-inhibitor 0.8596
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5436
Ames test Non AMES toxic 0.9077
Carcinogenicity Non-carcinogens 0.9003
Biodegradation Not ready biodegradable 0.9944
Rat acute toxicity 4.6023 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7959
hERG inhibition (predictor II) Non-inhibitor 0.8176
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral
CapsuleOral
LiquidIntravenous
LiquidIntravenous
Solution / dropsOral
Solution / dropsOral
Prices
Unit descriptionCostUnit
One-Alpha 2 mcg/ml17.28USDml
One-Alpha 2 mcg/ml Drops5.39USDml
One-Alpha 1 mcg Capsule1.41USDcapsule
One-Alpha 0.25 mcg Capsule0.47USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point136 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.00163ALOGPS
logP6.68ALOGPS
logP5.82ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)14.39ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area40.46 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity124.7 m3·mol-1ChemAxon
Polarizability50.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01518
PubChem Compound5282181
PubChem Substance46505115
ChemSpider4445376
PharmGKBPA164746469
Drug Product Database474517
ATC CodesA11CC03
AHFS Codes
  • 88:16.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
CalcipotriolVitamin D Analogs may enhance the adverse/toxic effect of other Vitamin D Analogs. Avoid combined use of multiple vitamin D analogs (at pharmacologic doses). Prescribing information for calcitriol, doxercalciferol, paricalcitol, and alfacalcidol each specifically cautions against such combined use.
CholecalciferolVitamin D analogs may enhance the adverse/toxic effect of other Vitamin D analogs. Avoid combined use of multiple vitamin D analogs (at pharmacologic doses). Prescribing information for calcitriol, doxercalciferol, paricalcitol, and alfacalcidol each specifically cautions against such combined use. Though not specified in the prescribing information for calcipotriene, cholecalciferol, and ergocalciferol, each contains warnings regarding the potential for vitamin D toxicity.
ColesevelamBile acid sequestrants such as colesevelam may decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Monitor plasma calcium concentrations in patients receiving combined therapy with these agents. This is particularly important in patients receiving higher doses of a bile acid sequestant (i.e., 30 g/day or more of cholestyramine or equivalent) or in patients experiencing bile acid sequestrant-induced steatorrhea. Specific recommendations regarding the separation of administration of these agents are not defined; however, it would seem prudent to separate the administration of these agents by several hours to minimize the potential risk of interaction. Similar precautions do not apply to parenterally administered vitamin D analogs.
Food InteractionsNot Available

Targets

1. Vitamin D3 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Vitamin D3 receptor P11473 Details

References:

  1. Reinhart GA: Vitamin D analogs: novel therapeutic agents for cardiovascular disease? Curr Opin Investig Drugs. 2004 Sep;5(9):947-51. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Fujishima T, Tsuji G, Tanaka C, Harayama H: Novel vitamin D receptor ligands having a carboxyl group as an anchor to arginine 274 in the ligand-binding domain. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):60-2. Epub 2010 May 6. Pubmed

2. 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial O15528 Details

References:

  1. Uchida E, Kagawa N, Sakaki T, Urushino N, Sawada N, Kamakura M, Ohta M, Kato S, Inouye K: Purification and characterization of mouse CYP27B1 overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL/ES. Biochem Biophys Res Commun. 2004 Oct 15;323(2):505-11. Pubmed

Carriers

1. Vitamin D-binding protein

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Vitamin D-binding protein P02774 Details

References:

  1. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999 Feb 19;96(4):507-15. Pubmed
  2. Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C: A structural basis for the unique binding features of the human vitamin D-binding protein. Nat Struct Biol. 2002 Feb;9(2):131-6. Pubmed
  3. Houghton LA, Vieth R: The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006 Oct;84(4):694-7. Pubmed
  4. Yamamoto N, Naraparaju VR: Vitamin D3-binding protein as a precursor for macrophage activating factor in the inflammation-primed macrophage activation cascade in rats. Cell Immunol. 1996 Jun 15;170(2):161-7. Pubmed
  5. Yamamoto N, Naraparaju VR: Role of vitamin D3-binding protein in activation of mouse macrophages. J Immunol. 1996 Aug 15;157(4):1744-9. Pubmed

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Drug created on July 26, 2007 06:34 / Updated on September 16, 2013 17:14