Identification

Name
Alfacalcidol
Accession Number
DB01436
Type
Small Molecule
Groups
Approved, 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
  • (5Z,7e)-9,10-Seco-5,7,10(19)-cholestatrien-1alpha,3beta-diol
  • 1-hydroxycholecalciferol
  • 1alpha-Hydroxy-vitamin D3
  • 1alpha-hydroxycholecalciferol
  • 1alpha-hydroxyvitamin D3
  • 9,10-Secocholesta-5,7,10(19)-triene-1alpha,3beta-diol
  • Alfacalcidolum
  • Alsiodol
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
One Alpha Caps 0.25mcgCapsule0.25 mcgOralLeo Pharma1980-12-31Not applicableCanada
One Alpha Caps 1mcgCapsule1 mcgOralLeo Pharma1980-12-31Not applicableCanada
One-alphaSolution / drops2 mcgOralLeo Pharma2000-12-04Not applicableCanada
One-alphaLiquid2 mcgIntravenousLeo Pharma2001-02-20Not applicableCanada
One-alphaCapsule0.5 mcgOralLeo PharmaNot applicableNot applicableCanada
One-alpha Sol 0.2mcg/mlLiquid.2 mcgOralLeo Pharma1989-12-312000-12-04Canada
International/Other Brands
Alsiodol / One Alpha
Categories
UNII
URQ2517572
CAS number
41294-56-8
Weight
Average: 400.6371
Monoisotopic: 400.334130652
Chemical Formula
C27H44O2
InChI Key
OFHCOWSQAMBJIW-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[[email protected]@H](C)[[email protected]@]1([H])CC[[email protected]@]2([H])\C(CCC[[email protected]]12C)=C\C=C1\C[[email protected]@H](O)C[[email protected]](O)C1=C

Pharmacology

Indication

Alfacalcidol is an active metabolite of Vitamin D, which performs important functions in regulation of the calcium balance and the bone metabolism.

Structured Indications
Pharmacodynamics

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.

Mechanism of action

The 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.

TargetActionsOrganism
AVitamin D3 receptor
agonist
Human
U25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrialNot AvailableHuman
URetinoic acid receptor RXR-alphaNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Hypercalcemia - 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
Magnesium HydroxideThe serum concentration of Magnesium Hydroxide can be increased when it is combined with Alfacalcidol.Approved
Magnesium oxideThe serum concentration of Magnesium oxide can be increased when it is combined with Alfacalcidol.Approved
Magnesium salicylateThe serum concentration of Magnesium salicylate can be increased when it is combined with Alfacalcidol.Approved
Magnesium SulfateThe serum concentration of Magnesium Sulfate can be increased when it is combined with Alfacalcidol.Approved, Vet Approved
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB15504
KEGG Drug
D01518
PubChem Compound
5282181
PubChem Substance
46505115
ChemSpider
4445376
ChEBI
31186
ChEMBL
CHEMBL1601669
PharmGKB
PA164746469
ATC Codes
A11CC03 — AlfacalcidolM05BB06 — Alendronic acid and alfacalcidol, sequential
AHFS Codes
  • 88:16.00 — Vitamin D

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentGraves Diseases1
2RecruitingTreatmentAutosomal Dominant Hypocalcemia / Autosomal Dominant Hypocalcemia or OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment1
2Unknown StatusTreatmentCalcifications, Vascular1
3CompletedTreatmentMuscle Weakness1
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
3CompletedTreatmentBone destruction1
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hyperparathyroidism, Secondary1
4CompletedTreatmentFalls / Osteopenia / Postmenopausal Osteoporosis (PMO)1
4CompletedTreatmentSystemic Lupus Erythematosus (SLE)1
4Not Yet RecruitingTreatmentGlomerulonephritis minimal lesion1
4RecruitingTreatmentElderly Infection / Frail Elderly Syndrome1
4RecruitingTreatmentType 2 Diabetic Nephropathy1
4Unknown StatusTreatmentBone destruction1
4WithdrawnPreventionAgeing / Chronic Renal Insufficiency / Falls, Accidental1
Not AvailableCompletedTreatmentAlfacalcidol, Secondary Hyperparathyroidism, Hemodialysis1
Not AvailableCompletedTreatmentHyperparathyroidism, Secondary1
Not AvailableRecruitingTreatmentBone destruction1
Not AvailableTerminatedTreatmentChronic Kidney Disease (CKD) / Deficiency, Vitamin D / Hyperparathyroidism, Secondary1
Not AvailableUnknown StatusTreatmentArthroplasty, Replacement, Hip / Bone Density1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral0.25 mcg
CapsuleOral1 mcg
CapsuleOral0.5 mcg
LiquidIntravenous2 mcg
Solution / dropsOral2 mcg
LiquidOral.2 mcg
Prices
Unit descriptionCostUnit
One-Alpha 2 mcg/ml17.28USD ml
One-Alpha 2 mcg/ml Drops5.39USD ml
One-Alpha 1 mcg Capsule1.41USD capsule
One-Alpha 0.25 mcg Capsule0.47USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)136 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.00163 mg/mLALOGPS
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
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9865
Blood Brain Barrier+0.9142
Caco-2 permeable+0.7866
P-glycoprotein substrateSubstrate0.7469
P-glycoprotein inhibitor INon-inhibitor0.5785
P-glycoprotein inhibitor IIInhibitor0.5574
Renal organic cation transporterNon-inhibitor0.7945
CYP450 2C9 substrateNon-substrate0.8188
CYP450 2D6 substrateNon-substrate0.8945
CYP450 3A4 substrateSubstrate0.7656
CYP450 1A2 substrateNon-inhibitor0.8249
CYP450 2C9 inhibitorNon-inhibitor0.8802
CYP450 2D6 inhibitorNon-inhibitor0.9434
CYP450 2C19 inhibitorNon-inhibitor0.7466
CYP450 3A4 inhibitorNon-inhibitor0.8596
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5436
Ames testNon AMES toxic0.9077
CarcinogenicityNon-carcinogens0.9003
BiodegradationNot ready biodegradable0.9944
Rat acute toxicity4.6023 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7959
hERG inhibition (predictor II)Non-inhibitor0.8176
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as vitamin d and derivatives. These are compounds containing a secosteroid backbone, usually secoergostane or secocholestane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Vitamin D and derivatives
Direct Parent
Vitamin D and derivatives
Alternative Parents
Triterpenoids / Secondary alcohols / Cyclic alcohols and derivatives / Hydrocarbon derivatives
Substituents
Triterpenoid / Cyclic alcohol / Secondary alcohol / Organic oxygen compound / Hydrocarbon derivative / Organooxygen compound / Alcohol / Aliphatic homopolycyclic compound
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
diol, seco-cholestane, D3 vitamins, hydroxycalciol (CHEBI:31186) / Vitamin D3 and derivatives (LMST03020231)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Recruited to promoters via its interaction with BAZ1B...
Gene Name
VDR
Uniprot ID
P11473
Uniprot Name
Vitamin D3 receptor
Molecular Weight
48288.64 Da
References
  1. Reinhart GA: Vitamin D analogs: novel therapeutic agents for cardiovascular disease? Curr Opin Investig Drugs. 2004 Sep;5(9):947-51. [PubMed:15503649]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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. doi: 10.1016/j.jsbmb.2010.04.020. Epub 2010 May 6. [PubMed:20435140]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Iron ion binding
Specific Function
Catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D) to 1-alpha,25-dihydroxyvitamin D3 (1,25(OH)2D) plays an important role in normal bone growth, calcium metabolism, and tissue differentiation.
Gene Name
CYP27B1
Uniprot ID
O15528
Uniprot Name
25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial
Molecular Weight
56503.475 Da
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:15369780]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
Gene Name
RXRA
Uniprot ID
P19793
Uniprot Name
Retinoic acid receptor RXR-alpha
Molecular Weight
50810.835 Da
References
  1. Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Garcia-Ordonez RD, Pascal BD, Burris TP, Dodge JA, Griffin PR: Hydrogen/deuterium exchange reveals distinct agonist/partial agonist receptor dynamics within vitamin D receptor/retinoid X receptor heterodimer. Structure. 2010 Oct 13;18(10):1332-41. doi: 10.1016/j.str.2010.07.007. [PubMed:20947021]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin transporter activity
Specific Function
Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.
Gene Name
GC
Uniprot ID
P02774
Uniprot Name
Vitamin D-binding protein
Molecular Weight
52963.025 Da
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:10052453]
  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:11799400]
  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:17023693]
  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:8660814]
  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:8759764]

Drug created on July 26, 2007 06:34 / Updated on October 21, 2017 19:30