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Calcitriol (INN), also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D₃, is the hormonally active metabolite of vitamin D with three hydroxyl groups (abbreviated 1,25-(OH)₂D₃ or simply 1,25(OH)₂D).^[6] It was first identified by Michael F. Holick in work published in 1971.^[7] Calcitriol increases the level of calcium (Ca²⁺) in the blood by increasing the uptake of calcium from the gut into the blood, increasing reabsorption of calcium by the kidneys, and possibly increasing the release of calcium into the blood from bone.^[8]

Nomenclature

Calcitriol usually refers specifically to 1,25-dihydroxycholecalciferol. Because cholecalciferol already has one hydroxyl group, only two are further specified in the nomenclature.

Pharmaceutical trade names

Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott), Decostriol (Mibe, Jesalis), Biowoz (Solmarc) and Vectical (Galderma), Rolsical (Sun Pharma).

Function

Calcitriol increases blood calcium levels ([Ca²⁺]) by:

Promoting absorption of dietary calcium from the gastrointestinal tract.
Increasing renal tubular reabsorption of calcium, thus reducing the loss of calcium in the urine.
Stimulating release of calcium from bone. For this it acts on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.^[9]

Calcitriol acts in concert with parathyroid hormone (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 inorganic phosphate (P_i), the counterion of Ca²⁺. The resulting decrease in serum phosphate causes hydroxyapatite (Ca₅(PO₄)₃OH) to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol (see below).^[8]

Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor, 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 cytoplasm. When calcitriol binds to the receptor, the ligand-receptor complex translocates to the cell nucleus, where it acts as a transcription factor promoting the expression of a gene encoding a calcium binding protein. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca²⁺) from the intestine across the intestinal mucosa into the blood.^[8]

The maintenance of electroneutrality requires that the transport of Ca²⁺ ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate. Thus calcitriol also stimulates the intestinal absorption of phosphate.^[8]

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.^[8] 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.

Calcitriol also inhibits the release of calcitonin,^{[citation needed]} a hormone which reduces blood calcium primarily by inhibiting calcium release from bone.^[8] (The effect of calcitonin on renal excretion is disputed.)^[10]

Biosynthesis and its regulation

Calcitriol is produced in the cells of the proximal tubule of the nephron in the kidneys by the action of 25-hydroxyvitamin D₃ 1-alpha-hydroxylase, a mitochondrial oxygenase and an enzyme which catalyzes the hydroxylation of 25-hydroxycholecalciferol (calcifediol). The activity of the enzyme is stimulated by PTH. The reaction is an important control point in Ca²⁺ homeostasis.^[8]

The production of calcitriol is also increased by prolactin, a hormone which stimulates lactogenesis (the formation of milk in mammary glands), 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 FGF-23 by osteocyte cells in bone.^{[citation needed]}

Metabolism

Calcitriol becomes calcitroic acid through the action of 24-hydroxylase. Calcitroic acid is excreted in the urine.^{[citation needed]}

Medical use

Calcitriol is prescribed for:^[11]

Treatment of hypocalcaemia – hypoparathyroidism, osteomalacia (adults), rickets (infants, children), renal osteodystrophy, chronic kidney disease
Treatment of osteoporosis
Prevention of corticosteroid-induced osteoporosis

Calcitriol is also sometimes used topically in the treatment of psoriasis, however the evidence to support its efficacy is not well established.^[12] The vitamin D analogue calcipotriol 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.^[13]

Calcitriol is also administered orally for the treatment of psoriasis^[14] and psoriatic arthritis.^[15]

Adverse effects

The main adverse drug reaction associated with calcitriol therapy is hypercalcemia – early symptoms include: nausea, vomiting, constipation, anorexia, apathy, headache, thirst, pruritus, sweating, and/or polyuria. Compared to other vitamin D compounds in clinical use (cholecalciferol, ergocalciferol), calcitriol has a higher risk of inducing hypercalcemia. However, such episodes may be shorter and easier to treat due to its relatively short half-life.^[11]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway (view / edit)]]

File:VitaminDSynthesis WP1531.png

Vitamin D Synthesis Pathway (view / edit)

^ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Additional images

Calcitriol synthesis

References

^ Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.
^ Wolters Kluwer, Stedman's Medical Dictionary, Wolters Kluwer.
^ Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.
^ Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt.
^ Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster.
^ "Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)" reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.
^ Holick, MF; Schnoes, HK; Deluca, HF; Suda, T; Cousins, RJ (1971). "Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine". Biochemistry. 10 (14): 2799–804. doi:10.1021/bi00790a023. PMID 4326883.
^ ^a ^b ^c ^d ^e ^f ^g 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.
^ 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 978-0-07-159991-7. Available online at AccessMedicine.com, purchase required.
^ Carney SL (1997). "Calcitonin and human renal calcium and electrolyte transport". Miner Electrolyte Metab. 23 (1): 43–7. PMID 9058369.
^ ^a ^b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
^ Calcitriol. In: Klasco RK, editor. Drugdex system. vol 128. Greenwood Village (CO): Thomson Micromedex; 2006.
^ Nagpal, S.; Na, S.; Rathnachalam, R. (2005). "Noncalcemic Actions of Vitamin D Receptor Ligands". Endocrine Reviews. 26 (5): 662–687. doi:10.1210/er.2004-0002. PMID 15798098. .
^ Smith, E. L.; Pincus, S. H.; Donovan, L.; Holick, M. F. (1988). "A novel approach for the evaluation and treatment of psoriasis". Journal of the American Academy of Dermatology. 19 (3): 516–528. doi:10.1016/S0190-9622(88)70207-8. PMID 2459166.
^ Huckins, D.; Felson, D. T.; Holick, M. (1990). "Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: A pilot study". Arthritis & Rheumatism. 33 (11): 1723. doi:10.1002/art.1780331117.

UpToDate Contents

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1. 慢性腎臓病に伴う骨・ミネラル代謝異常（CKD-MBD）の概要 overview of chronic kidney disease mineral bone disease ckd mbd
2. 乾癬の治療 treatment of psoriasis
3. 低カルシウム血症の治療 treatment of hypocalcemia
4. ビタミンD欠乏症の原因および抵抗性 causes of vitamin d deficiency and resistance
5. ミルク・アルカリ症候群 the milk alkali syndrome

English Journal

Dual antiplasmodial activity of vitamin D3 and its analog, 22-oxacalcitriol, by direct and indirect mechanisms.

Yamamoto K1, Iwagami M2, Seki T3, Kano S2, Ota N3, Ato M4.
Parasitology international.Parasitol Int.2017 Apr;66(2):89-99. doi: 10.1016/j.parint.2016.11.015. Epub 2016 Dec 2.
Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 a
PMID 27919743

Vitamin D-binding protein as it is understood in 2016: is it a critical key with which to help to solve the calcitriol conundrum?

Davey RX1.
Annals of clinical biochemistry.Ann Clin Biochem.2017 Mar;54(2):199-208. doi: 10.1177/0004563216677100. Epub 2016 Dec 11.
Background The misnamed 'vitamin' D is actually the hormone calcitriol (1,25 dihydroxyhydroxyvitamin D). It has a central regulatory role in calcium metabolism, and more widely in the immune system. The prohormone calcifediol (25 hydroxyvitamin D) is more easily measured in the laboratory and is the
PMID 27742848

Research on kidney and mineral metabolism in Japan: past, present, and future.

Mizobuchi M1, Ogata H2, Koiwa F3, Kinugasa E2, Akizawa T4,5.
Clinical and experimental nephrology.Clin Exp Nephrol.2017 Mar;21(Suppl 1):4-8. doi: 10.1007/s10157-016-1366-5. Epub 2016 Dec 22.
Since the identification of the kidney was the main site for the synthesis of calcitriol (1α, 25-dihydroxycholecalciferol), research on chronic kidney disease (CKD)-associated mineral metabolism disorders and their management has made rapid progress. Various active analogues of calcitriol have clin
PMID 28005175

Japanese Journal

副甲状腺内カルシトリオール局注療法（ｐｅｒｃｕｔａｎｅｏｕｓ　ｃａｌｃｉｔｒｉｏｌ　ｉｎｊｅｃｔｉｏｎ　ｔｈｅｒａｐｙ）が著効した二次性副甲状腺機能こう進症の１例

田中元子,伊藤和子,松下和徳,松下和孝,野々口博史,冨田公夫
日本透析医学会雑誌 36(5), 353-358, 2003
… 注入薬剤は, 副甲状腺インターベンション研究会より助成をうけ, Abbott社製Calcijex (1μg/mL) を使用した. …
NAID 130003721707

二次性副甲状腺機能こう進症における異所性副甲状腺に対しＰＣＩＴ（ｐｅｒｃｕｔａｎｅｏｕｓ　ｃａｒｃｉｔｒｉｏｌ　ｉｎｊｅｃｔｉｏｎ　ｔｈｅｒａｐｙ）が有効であった１症例

國松佳奈,角田隆俊,藤崎智隆,菅野勝寛,後藤巨木,田中礼佳,鍵和田直子,但木太,北村真,堺秀人,黒川清,斎藤明
日本透析医学会雑誌 34(12), 1501-1504, 2001
症例は65歳, 男性. 慢性糸球体腎炎を原疾患とし, 血液透析16年目に二次性副甲状腺機能亢進症 (2°HPT) を合併し副甲状腺亜全摘 (PTx: parathyroidectomy)+左下腿自家移植術を施行したが, 術後右反回神経麻痺を合併した. 術後5年目に骨関節痛にて外来受診し, 2° HPTの再発を認めた. 左右の大腿静脈採血では, 右738pg/ml, 左762pg/mlと濃度に有意差 …
NAID 130003875064

Related Pictures

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★リンクテーブル★

リンク元	「カルシトリオール」

「カルシトリオール」

Calcitriol
Clinical data
Pronunciation	US /ˌkælsᵻˈtraɪ.ɒl/;; UK /kælˈsɪtri.ɒl/
Trade names	Rocaltrol, Calcijex, Decostriol
MedlinePlus	a682335
Pregnancy; category	AU: B3; US: C (Risk not ruled out); ;
Routes of; administration	Oral, IV, topical
ATC code	A11CC04 (WHO) D05AX03 (WHO);
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Protein binding	99.9%
Metabolism	Renal
Biological half-life	5–8 hours (adults), 27 hours (children)
Excretion	Faeces (50%), urine (16%)
Identifiers
	IUPAC name (1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R)-6-hydroxy-6-methyl-heptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H- inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol;
CAS Number	32222-06-3 ;
PubChem CID	5280453;
IUPHAR/BPS	2779;
DrugBank	DB00136 ;
ChemSpider	4444108 ;
UNII	FXC9231JVH;
ChEBI	CHEBI:17823 ;
ChEMBL	CHEMBL846 ;
ECHA InfoCard	100.046.315
Chemical and physical data
Formula	C27H44O3
Molar mass	416.64 g/mol
3D model (Jmol)	Interactive image;
	SMILES C[C@H](CCCC(C)(C)O)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C ;
	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 ; Key:GMRQFYUYWCNGIN-NKMMMXOESA-N ;
(verify)

　　[★]

英: calcitriol, 1α,25-(OH)2-D3
同: 1α,25-ジヒドロキシコレカルシフェロール 1α,25-dihydroxycholecalciferol; 1α,25-ジヒドロキシビタミンD3 1α,25-dihydroxyvitamin D3
商: Calcijex; オタノール、カルシオロール、カルシタロール、カルデミン、カルトール、カルミサール、チコカロール、トルシトリン、ヒポテリオール、フルスタン、ホーネル、リストール、ロカルシトール、ロカルトロール Rocaltrol
関: 1,25-ジヒドロキシビタミンD3、1,25-ジヒドロキシコレカルシフェロール。ビタミンＡ及びＤ剤

[WikiPathways-16] The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

[Dorlands-1] Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.

[Stedmans-2] Wolters Kluwer, Stedman's Medical Dictionary, Wolters Kluwer.

[MW_Medical-3] Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.

[AHD-4] Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt.

[MWU-5] Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster.

[6] "Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)" reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.

[7] Holick, MF; Schnoes, HK; Deluca, HF; Suda, T; Cousins, RJ (1971). "Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine". Biochemistry. 10 (14): 2799–804. doi:10.1021/bi00790a023. PMID 4326883.

[Voet-8] ^ ^a ^b ^c ^d ^e ^f ^g 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.

[9] 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 978-0-07-159991-7. Available online at AccessMedicine.com, purchase required.

[pmid9058369-10] Carney SL (1997). "Calcitonin and human renal calcium and electrolyte transport". Miner Electrolyte Metab. 23 (1): 43–7. PMID 9058369.

[AMH2006-11] Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

[MicromedexDrugdex-12] Calcitriol. In: Klasco RK, editor. Drugdex system. vol 128. Greenwood Village (CO): Thomson Micromedex; 2006.

[13] Nagpal, S.; Na, S.; Rathnachalam, R. (2005). "Noncalcemic Actions of Vitamin D Receptor Ligands". Endocrine Reviews. 26 (5): 662–687. doi:10.1210/er.2004-0002. PMID 15798098. .

[14] Smith, E. L.; Pincus, S. H.; Donovan, L.; Holick, M. F. (1988). "A novel approach for the evaluation and treatment of psoriasis". Journal of the American Academy of Dermatology. 19 (3): 516–528. doi:10.1016/S0190-9622(88)70207-8. PMID 2459166.

[15] Huckins, D.; Felson, D. T.; Holick, M. (1990). "Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: A pilot study". Arthritis & Rheumatism. 33 (11): 1723. doi:10.1002/art.1780331117.

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Calcijex