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Identification
Name Calcitriol
Accession Number DB00136 (APRD00246, NUTR00003)
Type small molecule
Groups approved, 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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
1,25-(OH)<sub>2</sub>D3
1,25-dihydroxycholecalciferol
Salts Not Available
Brand names
Name Company
Calcijex Abbott
Calcitriol Oral Solution Roxane
Decostriol Mibe Jena (Germany), Jesalis (Hong Kong, Thailand)
Rocaltrol Roche
Brand mixtures Not Available
Categories
  • Essential Vitamin
  • Antihypocalcemic Agents
  • Antihypoparathyroid Agents
  • Vitamins (Vitamin D)
  • Bone Density Conservation Agents
  • Calcium Channel Agonists
  • Vitamins
CAS number 32222-06-3
Weight Average: 416.6365
Monoisotopic: 416.329045274
Chemical Formula C27H44O3
InChI Key InChIKey=GMRQFYUYWCNGIN-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication Used 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.
Pharmacodynamics Calcitriol, 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 action The 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.
Absorption Rapidly absorbed from the intestine.
Volume of distribution Not Available
Protein binding 99.9%
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.

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Substrate Enzymes Product
Calcitriol
    		Calcitroic acid Details
    Route of elimination Enterohepatic 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 life 5-8 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]
    Toxicity LD50 (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
    Pathways Not Available
    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
    Form Route Strength
    Capsule Oral 0.25 mcg
    Capsule Oral 0.5 mcg
    Solution Intravenous 1 mcg/ml
    Solution Intravenous 2 mcg/ml
    Solution Oral 1 mcg/ml
    Prices
    Unit description Cost Unit
    Calcijex 2 mcg/ml 19.38 USD ml
    Calcijex 1 mcg/ml ampul 14.7 USD ml
    Calcijex 1 mcg/ml 10.68 USD ml
    Calcitriol 1 mcg/ml ampul 6.0 USD ml
    Vectical 3 mcg/g ointment 4.68 USD g
    Rocaltrol 0.5 mcg capsule 2.02 USD capsule
    Calcitriol 0.5 mcg capsule 1.97 USD capsule
    Rocaltrol 0.25 mcg capsule 1.46 USD capsule
    Calcitriol 0.25 mcg capsule 1.45 USD capsule
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    Country Patent Number Approved Expires (estimated)
    United States 6051567 2000-02-02 2020-02-02
    Properties
    State solid
    Experimental Properties
    Property Value Source
    melting point 113 °C PhysProp
    water solubility Insoluble Not Available
    logP 5 Not Available
    Predicted Properties
    Property Value Source
    water solubility 6.67e-03 g/l ALOGPS
    logP 5.51 ALOGPS
    logP 4.35 ChemAxon
    logS -4.8 ALOGPS
    pKa (strongest acidic) 14.39 ChemAxon
    pKa (strongest basic) -1.3 ChemAxon
    physiological charge 0 ChemAxon
    hydrogen acceptor count 3 ChemAxon
    hydrogen donor count 3 ChemAxon
    polar surface area 60.69 ChemAxon
    rotatable bond count 6 ChemAxon
    refractivity 126.53 ChemAxon
    polarizability 51.02 ChemAxon
    References
    Synthesis Reference Not Available
    General Reference Not Available
    External Links
    Resource Link
    KEGG Drug D00129 Link_out
    KEGG Compound C01673 Link_out
    ChEBI 17823 Link_out
    ChEMBL 17823 Link_out
    Therapeutic Targets Database DAP000289 Link_out
    PharmGKB PA448717 Link_out
    IUPHAR 2779 Link_out
    Guide to Pharmacology 2779 Link_out
    Drug Product Database 2245686 Link_out
    RxList http://www.rxlist.com/cgi/generic2/calcitri.htm Link_out
    Drugs.com http://www.drugs.com/cdi/calcitriol.html Link_out
    PDRhealth http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0265.shtml Link_out
    Wikipedia http://en.wikipedia.org/wiki/Calcitriol Link_out
    ATC Codes
    • A11CC04
    • D05AX03
    AHFS Codes
    • 88:16.00
    PDB Entries Not Available
    FDA label show (39.2 KB)
    MSDS show (74.7 KB)
    Interactions
    Drug Interactions
    Drug Interaction
    Cholecalciferol Vitamin 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.
    Colesevelam Bile 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.
    Telithromycin Telithromycin 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.
    Voriconazole Voriconazole, 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 Interactions Not Available
    Targets

    1. Vitamin D3 receptor

    Pharmacological action: yes
    Actions: antagonist

    Nuclear hormone receptor. VDR mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes

    Organism class: human
    UniProt ID: P11473 Link_out
    Gene: VDR Link_out
    Protein Sequence: FASTA
    Gene Sequence: FASTA
    SNPs: SNPJam Report Link_out

    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. Cytochrome P450 24A1, mitochondrial

    Actions: substrate, inducer

    Has a role in maintaining calcium homeostasis. Catalyzes the NADPH-dependent 24-hydroxylation of 25-hydroxyvitamin D(3) in the presence of adrenodoxin and NADPH-adrenodoxin reductase

    UniProt ID: Q07973 Link_out
    Gene: CYP24A1 Link_out
    Protein Sequence: FASTA
    Gene Sequence: FASTA
    SNPs: SNPJam Report Link_out

    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

    Actions: substrate, inducer

    Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

    UniProt ID: P08684 Link_out
    Gene: CYP3A4
    Protein Sequence: FASTA
    Gene Sequence: FASTA
    SNPs: SNPJam Report Link_out

    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
    Comments
    Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19