| Revision as of 13:20, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEBI', 'ChemSpiderID', 'DrugBank', 'StdInChI', 'StdInChIKey').← Previous edit |
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{{Short description|Active form of vitamin D}} |
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{{Drugbox |
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{{Use dmy dates|date=January 2024}} |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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| verifiedrevid = 456362405 |
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{{Infobox drug |
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| IUPAC_name = (1''R'',3''S'')- 5-<nowiki></nowiki>- <br />7a-methyl-2,3,3a,5,6,7-hexahydro-1''H''- inden-4-ylidene]ethylidene]-<br /> 4-methylidene-cyclohexane-1,3-diol |
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| Watchedfields = changed |
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| image = Calcitriol.svg |
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| verifiedrevid = 460772865 |
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| image = File:Calcitriol.svg |
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| width = 250 |
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| alt = |
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| image2 = Calcitriol3Dan.gif |
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| width2 = 250 |
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| alt2 = |
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| caption = |
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<!--Clinical data--> |
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<!-- Clinical data --> |
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| pronounce = {{IPAc-en|US|ˌ|k|æ|l|s|ᵻ|ˈ|t|r|aɪ|ɒ|l}};<ref name="Dorlands">{{Citation |author=Elsevier |author-link=Elsevier |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |postscript=.}}</ref><ref name="Stedmans">{{Citation |author=Wolters Kluwer |author-link=Wolters Kluwer |title=Stedman's Medical Dictionary |publisher=Wolters Kluwer |url=http://stedmansonline.com/ |postscript=.}}</ref><ref name="MW_Medical">{{Citation |author=Merriam-Webster |author-link=Merriam-Webster |title=Merriam-Webster's Medical Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/medical/ |postscript=.}}</ref><ref name="AHD">{{Citation |author=Houghton Mifflin Harcourt |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |postscript=. |access-date=25 September 2015 |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/ |archive-date=25 September 2015 |url-status=dead }}</ref><ref name="MWU">{{Citation |author=Merriam-Webster |author-link=Merriam-Webster |title=Merriam-Webster's Unabridged Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/unabridged/ |postscript=. |access-date=25 September 2015 |archive-date=25 May 2020 |archive-url=https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F |url-status=dead }}</ref> <br /> {{IPAc-en|UK|k|æ|l|ˈ|s|ɪ|t|r|i|ɒ|l}} |
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| tradename = Rocaltrol, Calcijex, Decostriol |
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| tradename = Rocaltrol, Calcijex, Decostriol, others |
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| Drugs.com = {{drugs.com|monograph|calcitriol}} |
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| MedlinePlus = a682335 |
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| MedlinePlus = a682335 |
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| DailyMedID = Calcitriol |
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| pregnancy_category = B3 <small>(])</small>, C <small>(])</small> |
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| pregnancy_AU = B3 |
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| legal_status = S4 <small>(Au)</small>, POM <small>(])</small> |
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| pregnancy_AU_comment = |
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| routes_of_administration = Oral, ], topical |
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| pregnancy_category = |
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| routes_of_administration = ], ]<ref name=AHFS2019/> |
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| class = |
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| ATC_prefix = A11 |
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| ATC_suffix = CC04 |
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| ATC_supplemental = {{ATC|D05|AX03}} |
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<!--Pharmacokinetic data--> |
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<!-- Legal status --> |
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| legal_AU = S4 |
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| legal_AU_comment = |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = Rx-only |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = |
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| legal_EU = |
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| legal_EU_comment = |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = |
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| bioavailability = |
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| protein_bound = 99.9% |
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| metabolism = ] |
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| metabolism = ] |
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| elimination_half-life = 5–8 hours |
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| metabolites = |
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| excretion = Renal |
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| onset = |
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| elimination_half-life = 5–8 hours (adults), 27 hours (children) |
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| duration_of_action = |
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| excretion = Faeces (50%), urine (16%) |
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<!--Identifiers--> |
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<!-- Identifiers --> |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 32222-06-3 |
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| CAS_number = 32222-06-3 |
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| CAS_supplemental = |
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| ATC_prefix = A11 |
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| ATC_suffix = CC04 |
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| PubChem = 5280453 |
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| IUPHAR_ligand = 2779 |
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| ATC_supplemental = {{ATC|D05|AX03}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| ChEBI = 17823 |
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| PubChem = 134070 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = DB00136 |
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| DrugBank = DB00136 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = FXC9231JVH |
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| UNII = FXC9231JVH |
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| KEGG = D00129 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 17823 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 846 |
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| ChEMBL = 846 |
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| NIAID_ChemDB = |
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| PDB_ligand = VDX |
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| synonyms = 1,25-dihydroxycholecalciferol, 1alpha,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D<sub>3</sub>, 1α,25-(OH)<sub>2</sub>D<sub>3</sub>, 1,25(OH)<sub>2</sub>D<ref name="Nomen1981">{{cite journal | vauthors = | title = IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981 | journal = European Journal of Biochemistry | volume = 124 | issue = 2 | pages = 223–227 | date = May 1982 | pmid = 7094913 | doi = 10.1111/j.1432-1033.1982.tb06581.x | doi-access = free }}</ref> |
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<!--Chemical data--> |
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<!-- Chemical and physical data --> |
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| IUPAC_name = (1''R'',3''S'')-5--7a-methyl-2,3,3a,5,6,7-hexahydro-1''H''- inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol |
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| C=27 | H=44 | O=3 |
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| C=27 | H=44 | O=3 |
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| molecular_weight = 416.64 g/mol |
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| smiles = O3C(=C)/C(=CC=C1CCC2(1CC2(C)CCCC(O)(C)C)C)C(O)C3 |
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| SMILES = C(CCCC(C)(C)O)1CC\21(CCC/C2=C\C=C/3\C(C(C3=C)O)O)C |
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| InChI = 1/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/t18-,22-,23-,24+,25+,27-/m1/s1 |
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| InChIKey = GMRQFYUYWCNGIN-ZVUFCXRFBQ |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChI_comment = |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = GMRQFYUYWCNGIN-NKMMMXOESA-N |
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| StdInChIKey = GMRQFYUYWCNGIN-NKMMMXOESA-N |
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| density = |
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| solubility = |
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| specific_rotation = |
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}} |
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}} |
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<!-- Definition and physiology --> |
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'''Calcitriol''' (]) ({{IPAc-en|US|ˌ|k|æ|l|s|ɨ|ˈ|t|r|aɪ|.|ɒ|l|}}; {{IPAc-en|UK|k|æ|l|ˈ|s|ɪ|t|r|i|.|ɒ|l}}), also called '''1,25-dihydroxycholecalciferol''' or '''1,25-dihydroxyvitamin D<sub>3</sub>''', is the hormonally active form of ] with three ]s (abbreviated '''1,25-(OH)<sub>2</sub>D<sub>3</sub>''' or simply '''1,25(OH)<sub>2</sub>D''').<ref>" reproduced at the ] website. Retrieved 21 March 2010.</ref> It increases the level of ] (Ca<sup>2+</sup>) in the ] by (1) increasing the uptake of calcium from the ] into the blood, (2) decreasing the transfer of calcium from blood to the ] by the ], and (3) increasing the release of calcium into the blood from ].<ref name=Voet>Voet, Donald; Voet, Judith G. (2004). ''Biochemistry. Volume one. Biomolecules, mechanisms of enzyme action, and metabolism'', 3rd edition, pp. 663–664. New York: John Wiley & Sons. ISBN 0-471-25090-2.</ref> |
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'''Calcitriol''' is a ] and the active form of ], normally made in the ].<ref>{{cite journal | vauthors = Plum LA, DeLuca HF | title = Vitamin D, disease and therapeutic opportunities | journal = Nature Reviews. Drug Discovery | volume = 9 | issue = 12 | pages = 941–955 | date = December 2010 | pmid = 21119732 | doi = 10.1038/nrd3318 | s2cid = 8894111 }}</ref><ref>{{cite book |title=Encyclopedia of Endocrine Diseases |date=2018 |publisher=Academic Press |isbn=9780128122006 |page=344 |url=https://books.google.com/books?id=nVh7DwAAQBAJ&pg=RA4-PA344 |language=en}}</ref><ref name="NIH-ODS-2020">{{cite web |title=Office of Dietary Supplements - Vitamin D |url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |website=ods.od.nih.gov |date=9 October 2020 |access-date=31 October 2020 |language=en}}</ref> It is also known as '''1,25-dihydroxycholecalciferol'''. It binds to and activates the ] in the nucleus of the cell, which then increases the expression of many genes.<ref name="Norman_2008">{{cite journal | vauthors = Norman AW | title = From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health | journal = The American Journal of Clinical Nutrition | volume = 88 | issue = 2 | pages = 491S–499S | date = August 2008 | pmid = 18689389 | doi = 10.1093/ajcn/88.2.491S | doi-access = free }}</ref> Calcitriol increases blood ] mainly by increasing the uptake of calcium from the ].<ref name=AHFS2019/> |
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<!-- Medication --> |
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== Nomenclature == |
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It can be given as a medication for the treatment of ] and ] due to ], low blood calcium due to ], ], ], and ],<ref name=AHFS2019/><ref name=BNF76/> and can be taken by mouth or by ].<ref name=AHFS2019>{{cite web |title=Calcitriol Monograph for Professionals |url=https://www.drugs.com/monograph/calcitriol.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=9 April 2019 |language=en}}</ref> Excessive amounts or intake can result in weakness, headache, nausea, constipation, ], and abdominal pain.<ref name=AHFS2019/><ref name=BNF76/> Serious side effects may include ] and ].<ref name=AHFS2019/> |
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Calcitriol usually refers specifically to 1,25-dihydroxycholecalciferol, but may also sometimes include ] (when specified).{{Citation needed|date=April 2010}} |
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<!-- History and culture --> |
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Because ] already has one alcohol group, only two are further specified in the nomenclature. |
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Calcitriol was identified as the active form of vitamin D in 1971 and the drug was approved for medical use in the United States in 1978.<ref name=AHFS2019/> It is available as a ].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=1050–1051|edition=76}}</ref> In 2022, it was the 254th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Calcitriol Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Calcitriol | access-date = 30 August 2024 }}</ref> It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> |
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==Medical use== |
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=== Pharmaceutical trade names === |
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Calcitriol is prescribed for:<ref name="AMH2006">{{cite book | veditors = Rossi S |title=Australian Medicines Handbook |year=2006 |location=Adelaide |isbn=978-0-9757919-2-9 |publisher=Australian Medicines Handbook Pty Ltd |title-link=Australian Medicines Handbook |last1=Rossi |first1=Simone }}</ref> |
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Calcitriol is marketed under various trade names including '''Rocaltrol''' (]), '''Calcijex''' (]) and '''Decostriol''' (Mibe, Jesalis). |
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* Treatment of ] – ], ] (adults), ] (infants, children), ], ] |
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* Treatment of ] |
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* Prevention of ] |
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Calcitriol has been used in an ointment for the treatment of ],<ref>{{cite journal | vauthors = Kircik L | title = Efficacy and safety of topical calcitriol 3 microg/g ointment, a new topical therapy for chronic plaque psoriasis | journal = Journal of Drugs in Dermatology | volume = 8 | issue = 8 Suppl | pages = s9-16 | date = August 2009 | pmid = 19702031 }}</ref> although the ] ] (calcipotriene) is more commonly used.<ref>{{cite journal | vauthors = Kin KC, Hill D, Feldman SR | title = Calcipotriene and betamethasone dipropionate for the topical treatment of plaque psoriasis | journal = Expert Review of Clinical Pharmacology | volume = 9 | issue = 6 | pages = 789–797 | date = June 2016 | pmid = 27089906 | doi = 10.1080/17512433.2016.1179574 | s2cid = 38261070 }}</ref> Calcitriol has also been given by mouth for the treatment of psoriasis<ref>{{cite journal | vauthors = Smith EL, Pincus SH, Donovan L, Holick MF | title = A novel approach for the evaluation and treatment of psoriasis. Oral or topical use of 1,25-dihydroxyvitamin D3 can be a safe and effective therapy for psoriasis | journal = Journal of the American Academy of Dermatology | volume = 19 | issue = 3 | pages = 516–528 | date = September 1988 | pmid = 2459166 | doi = 10.1016/S0190-9622(88)70207-8 }}</ref> and ].<ref>{{cite journal | vauthors = Huckins D, Felson DT, Holick M | title = Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: a pilot study | journal = Arthritis and Rheumatism | volume = 33 | issue = 11 | pages = 1723–1727 | date = November 1990 | pmid = 2242069 | doi = 10.1002/art.1780331117 | doi-access = }}</ref> Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed.<ref>{{cite journal | vauthors = Nagpal S, Na S, Rathnachalam R | title = Noncalcemic actions of vitamin D receptor ligands | journal = Endocrine Reviews | volume = 26 | issue = 5 | pages = 662–687 | date = August 2005 | pmid = 15798098 | doi = 10.1210/er.2004-0002 | doi-access = free }}.</ref> |
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== Function == |
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Calcitriol increases blood calcium levels ( ) by promoting absorption of dietary calcium from the ] and increasing ] reabsorption of calcium thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as ], causing them to release ], which in turn activates ].<ref>Bringhurst, F. R; Demay, Marie B.; Krane, Stephen M.; Kronenberg, Henry M. "Bone and Mineral Metabolism in Health and Disease", chapter 346 in Fauci, Anthony S.; Braunwald, E.; Kasper, D. L.; Hauser, S. L.; Longo D. L.; Jameson, J. L.; Loscalzo, J. (2008). ''Harrison's Principles of Internal Medicine'', 17th edition. New York: McGraw-Hill. ISBN 9780071599917. at AccessMedicine.com, purchase required.</ref> |
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==Adverse effects== |
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Calcitriol acts in concert with ] (PTH) in all three of these roles. For instance, PTH also stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete ] (P<sub>i</sub>), the ] of Ca<sup>2+</sup>. The resulting decrease in serum phosphate causes Ca<sub>5</sub>(PO<sub>4</sub>)<sub>3</sub>OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).<ref name=Voet/> |
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The main ] associated with calcitriol therapy is ] – early symptoms include: ], ], ], ], ], ], ], ], ], and/or ]. Compared to other vitamin D compounds in clinical use (], ]), calcitriol has a higher risk of inducing hypercalcemia. However, such episodes may be shorter and easier to treat due to its relatively short ].<ref name="AMH2006" /> |
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High calcitriol levels may also be seen in human disease states in patients not on supplementation. In someone with hypercalcaemia and high calcitriol levels, low intact ] levels are usually present. |
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The major conditions with hypercalcaemia due to elevated calcitriol levels are ], ] and ] where excess production occurs due to ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in ].<ref>{{cite journal | vauthors = Tebben PJ, Singh RJ, Kumar R | title = Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment | journal = Endocrine Reviews | volume = 37 | issue = 5 | pages = 521–547 | date = October 2016 | pmid = 27588937 | pmc = 5045493 | doi = 10.1210/er.2016-1070 }}</ref> |
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Other conditions producing similar findings including: |
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* Fungal infections; ''Pneumocystis jiroveci'', histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, candidiasis |
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* Other granulomatous conditions; ], ], acute granulomatous pneumonia, talc granuloma, silicone-induced granuloma, BCG-associated, granulomatous hepatitis, paraffin-associated granuloma |
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* Genetic conditions; Williams syndrome, pseudoxanthoma elasticum, ] (adult / infantile), SLC34A1 mutation |
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* Miscellaneous; mycobacterium avium, leprosy, lipoid pneumonia, cat scratch fever, berylliosis |
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Some plants contain glycosides of ]. Consumption of these glycosides by grazing animals leads to vitamin D toxicity, resulting in ], the deposition of excessive calcium in soft tissues. Three rangeland plants, '']'', '']'', and ''],'' are known to contain these glycosides. Of these, only ''C. diurnum'' is found in the U.S., mainly in Florida.<ref>{{cite web |title=Calcinogenic Glycosides |url=http://poisonousplants.ansci.cornell.edu/toxicagents/calglyco.html |website=Plants Poisonous to Livestock |publisher=Cornell Department of Animal Science |access-date=16 June 2021}}</ref> |
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== Mechanism of action == |
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Calcitriol increases blood calcium levels () by: |
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* Promoting absorption of dietary calcium from the ]. |
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* Increasing ] reabsorption of calcium, thus reducing the loss of calcium in the urine. |
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* Stimulating release of calcium from bone. For this it acts on the specific type of bone cells referred to as ], causing them to release ], which in turn activates ].<ref>{{cite book | vauthors = Bringhurst F, Demay MB, Krane SM, Kronenberg HM |chapter=Bone and Mineral Metabolism in Health and Disease |chapter-url=http://www.accessmedicine.com/content.aspx?aID=2882031 | veditors = Fauci AS, Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, Loscalzo J |title=Harrison's Principles of Internal Medicine |publisher=McGraw-Hill |edition=17th |year=2008 |isbn=978-0-07-159991-7 }}</ref> |
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Calcitriol acts in concert with ] (PTH) in all three of these roles. For instance, PTH also indirectly stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete ] (P<sub>i</sub>), the ] of {{chem|Ca|2+}}. The resulting decrease in serum phosphate causes hydroxyapatite (Ca<sub>5</sub>(PO<sub>4</sub>)<sub>3</sub>OH) to dissolve out of bone, thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).<ref name=Voet>{{cite book | vauthors = Voet D, Voet J |year=2004 |title=Biochemistry |volume=1 |chapter=Biomolecules, mechanisms of enzyme action, and metabolism |edition=3rd |pages= |publisher=Wiley |isbn=978-0-471-25090-6 |chapter-url=https://archive.org/details/biochemistry00voet_1/page/663 }}</ref> |
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Many of the effects of calcitriol are mediated by its interaction with the ], also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the ]. When calcitriol binds to the receptor, the ]-receptor complex translocates to the ], where it acts as a ] promoting the expression of a gene encoding a ]. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca<sup>2+</sup>) from the intestine across the ] into the blood.<ref name=Voet/> |
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Many of the effects of calcitriol are mediated by its interaction with the ], also called the vitamin D receptor or VDR.<ref name="PMID26681795">{{cite journal | vauthors = Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G | title = Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects | journal = Physiological Reviews | volume = 96 | issue = 1 | pages = 365–408 | date = January 2016 | pmid = 26681795 | pmc = 4839493 | doi = 10.1152/physrev.00014.2015 }}</ref> For instance, the unbound inactive form of the calcitriol receptor in intestinal epithelial cells resides in the ]. When calcitriol binds to the receptor, the ]-receptor complex translocates to the ], where it acts as a ] promoting the expression of a gene encoding a ]. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium ({{chem|Ca|2+}}) from the intestine across the ] into the blood.<ref name=Voet/> Alternative, ''non-genomic'' pathways may be mediated through either ] or VDR.<ref>{{cite journal | vauthors = Hii CS, Ferrante A | title = The Non-Genomic Actions of Vitamin D | journal = Nutrients | volume = 8 | issue = 3 | pages = 135 | date = March 2016 | pmid = 26950144 | pmc = 4808864 | doi = 10.3390/nu8030135 | doi-access = free }}</ref> |
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The maintenance of electroneutrality requires that the transport of Ca<sup>2+</sup> ions catalyzed by the intestinal epithelial cells be accompanied by ]s, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.<ref name=Voet/> |
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The maintenance of electroneutrality requires that the transport of {{chem|Ca|2+}} ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.<ref name=Voet/> |
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The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts.<ref name=Voet/> Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur. |
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The observation that calcitriol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum calcitriol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from calcitriol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts.<ref name=Voet/> Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur. |
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Calcitriol also inhibits the release of ],{{Citation needed|date=April 2010}} a hormone which reduces blood calcium primarily by inhibiting calcium release from bone.<ref name=Voet/> (The effect of calcitonin on renal excretion is disputed.)<ref name="pmid9058369">{{cite journal | author = Carney SL | title = Calcitonin and human renal calcium and electrolyte transport | journal = Miner Electrolyte Metab | volume = 23 | issue = 1 | pages = 43–7 | year = 1997 | pmid = 9058369 | url = | accessdate = }}</ref> |
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Calcitriol also inhibits the release of ],<ref>{{cite journal | vauthors = Peleg S, Abruzzese RV, Cooper CW, Gagel RF | title = Down-regulation of calcitonin gene transcription by vitamin D requires two widely separated enhancer sequences | journal = Molecular Endocrinology | volume = 7 | issue = 8 | pages = 999–1008 | date = August 1993 | pmid = 8232320 | doi = 10.1210/mend.7.8.8232320 | doi-access = free }}</ref> a hormone which reduces blood calcium primarily by inhibiting calcium release from bone.<ref name=Voet/> |
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== Biosynthesis and its regulation == |
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== Biosynthesis and its regulation == |
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Calcitriol is produced in the cells of the ] of the ] in the kidneys by the action of ], a ]l ] and an ] which catalyzes the ] of ]. The activity of the enzyme is stimulated by PTH. The reaction is an important control point in ].<ref name=Voet/> |
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Calcitriol is produced in the cells of the ] of the ] in the kidneys by the action of ], a ]l ] and an ] which catalyzes the ] of ] in the 1-alpha position. |
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The production of calcitriol is also increased by ], a hormone which stimulates ] (the formation of breast milk), a process which requires large amounts of calcium. It is decreased by high levels of serum phosphate and by an increase in the production of the hormone ] by osteocyte cells in bone.{{Citation needed|date=April 2010}} |
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The activity of this enzyme is stimulated by PTH. This is an important control point in ].<ref name=Voet/> Additional effects on the production of calcitriol include an increase by ], a hormone which stimulates ] (the formation of milk in ]), a process which requires large amounts of calcium.<ref>{{cite journal | vauthors = Ajibade DV, Dhawan P, Fechner AJ, Meyer MB, Pike JW, Christakos S | title = Evidence for a role of prolactin in calcium homeostasis: regulation of intestinal transient receptor potential vanilloid type 6, intestinal calcium absorption, and the 25-hydroxyvitamin D(3) 1alpha hydroxylase gene by prolactin | journal = Endocrinology | volume = 151 | issue = 7 | pages = 2974–2984 | date = July 2010 | pmid = 20463051 | pmc = 2903940 | doi = 10.1210/en.2010-0033 }}</ref> Activity is also decreased by high levels of serum phosphate and by an increase in the production of the hormone ] by osteocyte cells in bone.<ref name="RodriguezFGF23">{{cite journal | vauthors = Rodríguez-Ortiz ME, Rodríguez M | title = FGF23 as a calciotropic hormone | journal = F1000Research | volume = 4 | pages = 1472 | date = 2015 | pmid = 27081473 | pmc = 4815615 | doi = 10.12688/f1000research.7189.1 | doi-access = free }}</ref> |
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Calcitriol is also produced outside the kidney in small amounts by many other tissues including ] and activated ].<ref>{{cite journal | vauthors = Adams JS, Hewison M | title = Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase | journal = Archives of Biochemistry and Biophysics | volume = 523 | issue = 1 | pages = 95–102 | date = July 2012 | pmid = 22446158 | pmc = 3361592 | doi = 10.1016/j.abb.2012.02.016 }}</ref> |
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==Metabolism== |
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Calcitriol becomes ] through the action of ]. Calcitroic acid is excreted in the urine. |
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When the drug ] is used, 25-hydroxylation in the liver produces calcitriol as the active metabolite. This will produce greater effects than other vitamin D precursors in patients with kidney disease who have loss of the renal 1-alpha-hydroxylase.<ref name="ReferenceA"/> |
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==Medical use== |
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Calcitriol is prescribed for:<ref name="AMH2006">Rossi S, editor. ] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> |
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*Treatment of ] – ], ] (adults), ] (infants, children), ], chronic ] |
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*Treatment of ] |
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*Prevention of ]-induced osteoporosis |
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===Interactive pathway map=== |
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Calcitriol is also sometimes used topically in the treatment of ], however the evidence to support its efficacy is not well established.<ref name="MicromedexDrugdex">Calcitriol. In: Klasco RK, editor. Drugdex system. vol 128. Greenwood Village (CO): Thomson Micromedex; 2006.</ref> The vitamin D analogue ] is more commonly used for psoriasis. Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed.<ref>Nagpal S, Na S, Rathnachalam R (2005). . ''Endocrine Reviews'' '''26''' (5): 662–687. ]. {{PMID|15798098 }}.</ref> |
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{{VitaminDSynthesis WP1531|highlight=Calcitriol}} |
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==Adverse effects== |
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===Metabolism=== |
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The halflife of calcitriol in the body is measured in hours, unlike its precursor calcifediol, whose halflife is measured in weeks.<ref>{{cite journal | vauthors = Brandi ML | title = Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes | journal = Clinical Cases in Mineral and Bone Metabolism | volume = 7 | issue = 3 | pages = 243–250 | date = September 2010 | pmid = 22460535 | pmc = 3213838 }}</ref> Calcitriol is inactivated by further hydroxylation to form 1,24,25-trihydroxyvitamin D, ]. This occurs through the action of the CYP24A1 ].<ref>{{cite journal | vauthors = Jones G, Prosser DE, Kaufmann M | title = Cytochrome P450-mediated metabolism of vitamin D | journal = Journal of Lipid Research | volume = 55 | issue = 1 | pages = 13–31 | date = January 2014 | pmid = 23564710 | pmc = 3927478 | doi = 10.1194/jlr.R031534 |doi-access=free }}</ref> Calcitroic acid is more soluble in water and is excreted in bile and urine. |
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The main ] associated with calcitriol therapy is ] – early symptoms include: nausea, vomiting, constipation, ], ], headache, thirst, sweating, and/or ]). Compared to other vitamin D compounds in clinical use (], ]), calcitriol has a higher risk of inducing hypercalcaemia. However, such episodes may be shorter and easier to treat due to its relatively short ].<ref name="AMH2006" /> |
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==See also== |
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==History== |
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It was first identified in 1971 by ] working in the laboratory of ],<ref>{{cite journal | vauthors = Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ | title = Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine | journal = Biochemistry | volume = 10 | issue = 14 | pages = 2799–2804 | date = July 1971 | pmid = 4326883 | doi = 10.1021/bi00790a023 }}</ref><ref name="pmid4323790">{{cite journal | vauthors = Holick MF, Schnoes HK, DeLuca HF | title = Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 4 | pages = 803–804 | date = April 1971 | pmid = 4323790 | pmc = 389047 | doi = 10.1073/pnas.68.4.803 | doi-access = free | bibcode = 1971PNAS...68..803H }}</ref> and also by ] and colleagues.<ref name="pmid4325863">{{cite journal | vauthors = Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, ] | title = 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine | journal = Science | volume = 173 | issue = 3991 | pages = 51–54 | date = July 1971 | pmid = 4325863 | doi = 10.1126/science.173.3991.51 | s2cid = 35236666 | bibcode = 1971Sci...173...51N }}</ref> |
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* ] |
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* ] |
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* ] |
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It was approved for medical use in the United States in 1978.<ref name=AHFS2019/> |
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==Additional images== |
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<gallery> |
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Image:Calcitriol-Synthesis.png|Calcitriol synthesis |
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</gallery> |
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==References== |
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== Names == |
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Calcitriol refers specifically to 1,25-dihydroxycholecalciferol. Because ] already has one hydroxyl group, only two (1,25) are further specified in this nomenclature, but in fact there are three (1,3,25-triol), as indicated by the name ''calcitriol''. The 1-hydroxy group is in the alpha position, and this may be specified in the name, for instance in the abbreviation 1α,25-(OH)<sub>2</sub>D<sub>3</sub>.<ref name="Nomen1981"/> |
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{{reflist}} |
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Calcitriol is, strictly, the 1-hydroxylation product of ] (25-OH vitamin D<sub>3</sub>), derived from cholecalciferol (vitamin D<sub>3</sub>), rather than the product of hydroxylations of ] (vitamin D<sub>2</sub>).<ref name="Nomen1981"/> 1α,25-Dihydroxyergocalciferol (ercalcitriol) should be used for the vitamin D<sub>2</sub> product.<ref name="Nomen1981"/> However, the terminology of 1,25-dihydroxyvitamin D, or 1,25(OH)<sub>2</sub>D, is often used to refer to both types of active forms of vitamin D. Indeed, both bind to the vitamin D receptor and produce biological effects.<ref>{{cite journal | vauthors = Cantorna MT, Snyder L, Lin YD, Yang L | title = Vitamin D and 1,25(OH)2D regulation of T cells | journal = Nutrients | volume = 7 | issue = 4 | pages = 3011–3021 | date = April 2015 | pmid = 25912039 | pmc = 4425186 | doi = 10.3390/nu7043011 | doi-access = free }}</ref> In clinical use, the differences are unlikely to have major importance.<ref name="ReferenceA">{{cite journal | vauthors = Mazzaferro S, Goldsmith D, Larsson TE, Massy ZA, Cozzolino M | title = Vitamin D metabolites and/or analogs: which D for which patient? | journal = Current Vascular Pharmacology | volume = 12 | issue = 2 | pages = 339–349 | date = March 2014 | pmid = 23713876 | doi = 10.2174/15701611113119990024 }}</ref> |
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Calcitriol is marketed as a pharmaceutical for medical use under various brand names including Rocaltrol (]), Calcijex (]), Decostriol (Mibe, Jesalis), Vectical (]), and Rolsical (]).{{cn|date=October 2024}} |
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== References == |
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{{Reflist}} |
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{{Hormones}} |
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{{Hormones}} |
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{{Vitamin}} |
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{{Vitamins}} |
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{{Antipsoriatics}} |
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{{Vitamin D receptor modulators}} |
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{{Portal bar | Medicine}} |
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{{Authority control}} |
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{{DEFAULTSORT:Dihydroxycholecalciferol, 1,25-}} |
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