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Identification
NameCalcitriol
Accession NumberDB00136  (APRD00246, NUTR00003)
Typesmall molecule
Groupsapproved, nutraceutical
Description

Calcitriol or 1,25-dihydroxycholecalciferol (abbreviated 1,25-(OH)2-D3) is the active form of vitamin D found in the body (vitamin D3). Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott) and Decostriol (Mibe, Jesalis). It is produced in the kidneys via 25-hydroxyvitamin D-1 α-hydroxylase by conversion from 25-hydroxycholecalciferol (calcidiol). This is stimulated by a decrease in serum calcium, phosphate (PO43−) and parathyroid hormone (PTH) levels. It regulates calcium levels by increasing the absorption of calcium and phosphate from the gastrointestinal tract, increasing calcium and phosphate reabsorption in the kidneys and inhibiting the release of PTH. Calcitriol is also commonly used as a medication in the treatment of hypocalcemia and osteoporosis.

Structure
Thumb
Synonyms
SynonymLanguageCode
(1alpha,3beta,5Z,7e)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triolNot AvailableNot Available
(1S,3R,5Z,7e)-9,10-Secocholesta-5,7,10-triene-1,3,25-triolNot AvailableNot Available
(5Z,7e)-(1S,3R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triolNot AvailableNot Available
1-alpha-25-Dihydroxyvitamin D3Not AvailableNot Available
1,25-DHCCNot AvailableNot Available
1,25-dihydroxycholecalciferolNot AvailableNot Available
1alpha,25-DihydroxycholecalciferolNot AvailableNot Available
1alpha,25-Dihydroxyvitamin D3Not AvailableNot Available
1alpha,25(OH)2D3Not AvailableNot Available
1α,25-dihydroxycholecalciferolNot AvailableNot Available
1α,25-dihydroxyvitamin D3Not AvailableNot Available
1α,25(OH)2D3Not AvailableNot Available
5-{2-[1-(5-hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ylidene]-ethylidene}-4-methylene-cyclohexane-1,3-diolNot AvailableNot Available
CalcijexNot AvailableNot Available
CalcitriolNot AvailableNot Available
CalcitriolumNot AvailableNot Available
DecostriolNot AvailableNot Available
RocaltrolNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
CalcijexAbbott
Calcitriol Oral SolutionRoxane
DecostriolMibe Jena (Germany), Jesalis (Hong Kong, Thailand)
RocaltrolRoche
VecticalNot Available
Brand mixturesNot Available
Categories
CAS number32222-06-3
WeightAverage: 416.6365
Monoisotopic: 416.329045274
Chemical FormulaC27H44O3
InChI KeyGMRQFYUYWCNGIN-NKMMMXOESA-N
InChI
InChI=1S/C27H44O3/c1-18(8-6-14-26(3,4)30)23-12-13-24-20(9-7-15-27(23,24)5)10-11-21-16-22(28)17-25(29)19(21)2/h10-11,18,22-25,28-30H,2,6-9,12-17H2,1,3-5H3/b20-10+,21-11-/t18-,22-,23-,24+,25+,27-/m1/s1
IUPAC Name
(1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol
SMILES
C[C@H](CCCC(C)(C)O)[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; Tertiary Alcohols; Cyclic Alcohols and Derivatives; Polyamines
Substituentscyclohexanol; tertiary alcohol; 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
IndicationUsed to treat vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis. Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.
PharmacodynamicsCalcitriol, a pharmaceutical form of vitamin D, has anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Calcitriol has been found to be effective in the treatment of psoriasis when applied topically. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation in a number of malignant cell lines including human prostate cancer cells. Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of calcitriol, 1,25-(OH)2-D3, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of Mycobacterium tuberculosis. 1,25-(OH)2-D3 has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. It has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.
Mechanism of actionThe mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)2-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)2-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells.
AbsorptionRapidly absorbed from the intestine.
Volume of distributionNot Available
Protein binding99.9%
Metabolism

The first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3. The lactone appears to be the major metabolite circulating in humans.

SubstrateEnzymesProduct
Calcitriol
Not Available
Calcitroic acidDetails
Route of eliminationEnterohepatic recycling and biliary excretion of calcitriol occur. The metabolites of calcitriol are excreted primarily in feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces.
Half life5-8 hours
Clearance
  • 15.3 mL/hr/kg [pediatric patients (age range: 1.8 to 16 years) undergoing peritoneal dialysis receiving dose of 10.2 ng/kg (SD 5.5 ng/kg) for 2 months]
ToxicityLD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg; Overdose evident in elevated blood calcium levels causing symptoms of anorexia, nausea and vomiting, polyuria, polydipsia, weakness, pruritus, and nervousness, potentially with irreversible calcification of soft tissue in the kidney and liver.
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 + 0.9924
Blood Brain Barrier + 0.8524
Caco-2 permeable + 0.7812
P-glycoprotein substrate Substrate 0.7843
P-glycoprotein inhibitor I Non-inhibitor 0.6065
P-glycoprotein inhibitor II Non-inhibitor 0.6073
Renal organic cation transporter Non-inhibitor 0.8178
CYP450 2C9 substrate Non-substrate 0.8367
CYP450 2D6 substrate Non-substrate 0.9022
CYP450 3A4 substrate Substrate 0.7506
CYP450 1A2 substrate Non-inhibitor 0.9033
CYP450 2C9 substrate Non-inhibitor 0.8354
CYP450 2D6 substrate Non-inhibitor 0.9495
CYP450 2C19 substrate Non-inhibitor 0.7796
CYP450 3A4 substrate Non-inhibitor 0.813
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6175
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.9274
Biodegradation Not ready biodegradable 0.9937
Rat acute toxicity 5.1352 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8734
hERG inhibition (predictor II) Non-inhibitor 0.8579
Pharmacoeconomics
Manufacturers
  • Roxane laboratories inc
  • Teva pharmaceuticals usa inc
  • Validus pharmaceuticals llc
  • Abbott laboratories hosp products div
  • Akorn inc
  • App pharmaceuticals llc
  • Fresenius medical care north america
  • Genix therapeutics inc
  • Hospira inc
  • Luitpold pharmaceuticals inc
  • Lyne laboratories inc
  • Teva parenteral medicines inc
  • Galderma laboratories lp
Packagers
Dosage forms
FormRouteStrength
CapsuleOral0.25 mcg
CapsuleOral0.5 mcg
SolutionIntravenous1 mcg/ml
SolutionIntravenous2 mcg/ml
SolutionOral1 mcg/ml
Prices
Unit descriptionCostUnit
Calcijex 2 mcg/ml19.38USDml
Calcijex 1 mcg/ml ampul14.7USDml
Calcijex 1 mcg/ml10.68USDml
Calcitriol 1 mcg/ml ampul6.0USDml
Vectical 3 mcg/g ointment4.68USDg
Rocaltrol 0.5 mcg capsule2.02USDcapsule
Calcitriol 0.5 mcg capsule1.97USDcapsule
Rocaltrol 0.25 mcg capsule1.46USDcapsule
Calcitriol 0.25 mcg capsule1.45USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60515672000-02-022020-02-02
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point113-114Uskokovic, M.R., Narwid, T.A., lacobelli, J.A. and Baggiolini, E.; U.S. Patent 3,993,675; November 23, 1976; assigned to Hoffmann-La Roche, Inc.
water solubilityInsolubleNot Available
logP5Not Available
Predicted Properties
PropertyValueSource
water solubility6.67e-03 g/lALOGPS
logP5.51ALOGPS
logP4.35ChemAxon
logS-4.8ALOGPS
pKa (strongest acidic)14.39ChemAxon
pKa (strongest basic)-1.3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count3ChemAxon
polar surface area60.69ChemAxon
rotatable bond count6ChemAxon
refractivity126.53ChemAxon
polarizability51.02ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Raymond E. Conrow, “Process for preparation of calcitriol lactone and related intermediates.” U.S. Patent US5457245, issued April, 1994.

US5457245
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00129
KEGG CompoundC01673
ChEBI17823
ChEMBLCHEMBL846
Therapeutic Targets DatabaseDAP000289
PharmGKBPA448717
IUPHAR2779
Guide to Pharmacology2779
Drug Product Database2245686
RxListhttp://www.rxlist.com/cgi/generic2/calcitri.htm
Drugs.comhttp://www.drugs.com/cdi/calcitriol.html
PDRhealthhttp://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0265.shtml
WikipediaCalcitriol
ATC CodesA11CC04D05AX03
AHFS Codes
  • 88:16.00
PDB EntriesNot Available
FDA labelshow(39.2 KB)
MSDSshow(74.7 KB)
Interactions
Drug Interactions
Drug
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.
TelithromycinTelithromycin may reduce clearance of Calcitriol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Calcitriol if Telithromycin is initiated, discontinued or dose changed.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of calcitriol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of calcitriol if voriconazole is initiated, discontinued or dose changed.
Food InteractionsNot Available

Targets

1. Vitamin D3 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

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

Enzymes

1. 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Q07973 Details

References:

  1. Schuster I: Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta. 2010 Jul 7. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, Kalhorn TF, Watkins PB, Schuetz EG, Thummel KE: Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol. 2006 Jan;69(1):56-65. Epub 2005 Oct 5. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Lexicomp.

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Drug created on June 13, 2005 07:24 / Updated on September 24, 2013 10:42