Calcitriol

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Calcitriol
Calcitriol.svg
Calcitriol3Dan.gif
Clinical data
Pronunciation US: /ˌkælsɪˈtraɪɒl/ ; [1] [2] [3] [4] [5]
UK: /kælˈsɪtriɒl/
Trade names Rocaltrol, Calcijex, Decostriol, others
Other names1,25-dihydroxycholecalciferol, 1alpha,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D3, 1α,25-(OH)2D3, 1,25(OH)2D [6]
AHFS/Drugs.com Monograph
MedlinePlus a682335
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, intravenous [7]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 99.9%
Metabolism Kidney
Elimination half-life 5–8 hours (adults), 27 hours (children)
Excretion Faeces (50%), urine (16%)
Identifiers
  • (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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.046.315 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H44O3
Molar mass 416.646 g·mol−1
3D model (JSmol)
  • 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=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 Yes check.svgY
  • Key:GMRQFYUYWCNGIN-NKMMMXOESA-N Yes check.svgY
   (verify)

Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. [8] [9] [10] It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. [11] Calcitriol increases blood calcium mainly by increasing the uptake of calcium from the intestines. [7]

Contents

It can be given as a medication for the treatment of low blood calcium and hyperparathyroidism due to kidney disease, low blood calcium due to hypoparathyroidism, osteoporosis, osteomalacia, and familial hypophosphatemia, [7] [12] and can be taken by mouth or by injection into a vein. [7] Excessive amounts or intake can result in weakness, headache, nausea, constipation, urinary tract infections, and abdominal pain. [7] [12] Serious side effects may include high blood calcium and anaphylaxis. [7]

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. [7] It is available as a generic medication. [12] In 2022, it was the 254th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [13] [14] It is on the World Health Organization's List of Essential Medicines. [15]

Medical use

Calcitriol is prescribed for: [16]

Calcitriol has been used in an ointment for the treatment of psoriasis, [17] although the vitamin D analogue calcipotriol (calcipotriene) is more commonly used. [18] Calcitriol has also been given by mouth for the treatment of psoriasis [19] and psoriatic arthritis. [20] Research on the noncalcemic actions of calcitriol and other VDR-ligand analogs and their possible therapeutic applications has been reviewed. [21]

Adverse effects

The main adverse drug reaction associated with calcitriol therapy is hypercalcaemia – 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. [16]

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 parathyroid hormone levels are usually present.

The major conditions with hypercalcaemia due to elevated calcitriol levels are lymphoma, tuberculosis and sarcoidosis where excess production occurs due to ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages. [22] Other conditions producing similar findings including:

Some plants contain glycosides of 1,25-dihydroxycholecalciferol. Consumption of these glycosides by grazing animals leads to vitamin D toxicity, resulting in calcinosis, the deposition of excessive calcium in soft tissues. Three rangeland plants, Cestrum diurnum , Solanum malacoxylon , and Trisetum flavescens, are known to contain these glycosides. Of these, only C. diurnum is found in the U.S., mainly in Florida. [23]

Mechanism of action

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

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 (Pi), 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). [25]

Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor, also called the vitamin D receptor or VDR. [26] 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. [25] Alternative, non-genomic pathways may be mediated through either PDIA3 or VDR. [27]

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. [25]

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. [25] 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, [28] a hormone which reduces blood calcium primarily by inhibiting calcium release from bone. [25]

Biosynthesis and its regulation

Calcitriol synthesis Calcitriol-Synthesis.png
Calcitriol synthesis

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) in the 1-alpha position.

The activity of this enzyme is stimulated by PTH. This is an important control point in Ca2+ homeostasis. [25] Additional effects on the production of calcitriol include an increase by prolactin, a hormone which stimulates lactogenesis (the formation of milk in mammary glands), a process which requires large amounts of calcium. [29] Activity is also decreased by high levels of serum phosphate and by an increase in the production of the hormone FGF23 by osteocyte cells in bone. [30]

Calcitriol is also produced outside the kidney in small amounts by many other tissues including placenta and activated macrophages. [31]

When the drug alfacalcidol 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. [32]

Interactive pathway map

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

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|alt=Vitamin D Synthesis Pathway (view / edit)]]
Vitamin D Synthesis Pathway (view / edit)
  1. ↑ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Metabolism

The halflife of calcitriol in the body is measured in hours, unlike its precursor calcifediol, whose halflife is measured in weeks. [33] Calcitriol is inactivated by further hydroxylation to form 1,24,25-trihydroxyvitamin D, calcitroic acid. This occurs through the action of the CYP24A1 24-hydroxylase. [34] Calcitroic acid is more soluble in water and is excreted in bile and urine.

History

It was first identified in 1971 by Michael F. Holick working in the laboratory of Hector DeLuca, [35] [36] and also by Tony Norman and colleagues. [37]

It was approved for medical use in the United States in 1978. [7]

Names

Calcitriol refers specifically to 1,25-dihydroxycholecalciferol. Because cholecalciferol 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)2D3. [6]

Calcitriol is, strictly, the 1-hydroxylation product of calcifediol (25-OH vitamin D3), derived from cholecalciferol (vitamin D3), rather than the product of hydroxylations of ergocalciferol (vitamin D2). [6] 1α,25-Dihydroxyergocalciferol (ercalcitriol) should be used for the vitamin D2 product. [6] However, the terminology of 1,25-dihydroxyvitamin D, or 1,25(OH)2D, 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. [38] In clinical use, the differences are unlikely to have major importance. [32]

Calcitriol is marketed as a pharmaceutical for medical use under various brand names including Rocaltrol (Roche), Calcijex (Abbott), Decostriol (Mibe, Jesalis), Vectical (Galderma), and Rolsical (Sun Pharma).[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Calcitonin</span> Peptide hormone secreted by the thyroid

Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).

<span class="mw-page-title-main">Cholecalciferol</span> Vitamin D3, a chemical compound

Cholecalciferol, also known as vitamin D3 or colecalciferol, is a type of vitamin D that is produced by the skin when exposed to UVB light; it is found in certain foods and can be taken as a dietary supplement.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. It is a very rare disease. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes. The diagnosis is made with blood tests, and other investigations such as genetic testing depending on the results. The primary treatment of hypoparathyroidism is calcium and vitamin D supplementation. Calcium replacement or vitamin D can ameliorate the symptoms but can increase the risk of kidney stones and chronic kidney disease. Additionally, medications such as recombinant human parathyroid hormone or teriparatide may be given by injection to replace the missing hormone.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Bone resorption</span> Breakdown of bone tissue to be absorbed into the blood

Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.

<span class="mw-page-title-main">Secondary hyperparathyroidism</span> Medical condition

Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.

<span class="mw-page-title-main">Milk-alkali syndrome</span> Symptoms due to excess consumption of calcium and alkali

Milk-alkali syndrome (MAS), also referred to as calcium-alkali syndrome, is the third most common cause of elevated blood calcium levels (hypercalcemia). Milk-alkali syndrome is characterized by hypercalcemia, metabolic alkalosis, and acute kidney injury.

<span class="mw-page-title-main">Vitamin D receptor</span> Transcription factor activated by vitamin D

The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer with the retinoid-X receptor. The VDR heterodimer then enters the nucleus and binds to Vitamin D responsive elements (VDRE) in genomic DNA. VDR binding results in expression or transrepression of many specific gene products. VDR is also involved in microRNA-directed post transcriptional mechanisms. In humans, the vitamin D receptor is encoded by the VDR gene located on chromosome 12q13.11.

<span class="mw-page-title-main">Calcifediol</span> Chemical compound

Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 (abbreviated 25(OH)D3), is a form of vitamin D produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme vitamin D 25-hydroxylase. Calcifediol can be further hydroxylated by the enzyme 25(OH)D-1α-hydroxylase, primarily in the kidney, to form calcitriol (1,25-(OH)2D3), which is the active hormonal form of vitamin D.

<span class="mw-page-title-main">Calcitroic acid</span> Chemical compound

Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3) is a major metabolite of 1α,25-dihydroxyvitamin D3 (calcitriol). Around 1980, scientists first reported the isolation of calcitroic acid from the aqueous extract of radioactively treated animals' livers and intestines. Subsequent researches confirmed calcitroic acid to be a part of enterohepatic circulation. Often synthesized in the liver and kidneys, calcitroic acid is generated in the body after vitamin D is first converted into calcitriol, an intermediate in the fortification of bone through the formation and regulation of calcium in the body. These pathways managed by calcitriol are thought to be inactivated through its hydroxylation by the enzyme CYP24A1, also called calcitriol 24-hydroxylase. Specifically, It is thought to be the major route to inactivate vitamin D metabolites. The hydroxylation and oxidation reactions will yield either calcitroic acid via the C24 oxidation pathway or 1,25(OH2)D3-26,23-lactone via the C23 lactone pathway. However, the only scientifically known formation of calcitroic acid is through an oxidative reaction of the 1ɑ,25-dihydroxy vitamin D3. The positions of C24 and C23 undergo multiple oxidative reactions. Thus, causing the large and small side chains of 1ɑ,25-dihydroxy vitamin D3 to cleave off and form calcitroic acid.

<span class="mw-page-title-main">CYP24A1</span>

Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D3). It has also been identified as vitamin D3 24-hydroxylase.(EC 1.14.15.16)

<span class="mw-page-title-main">24,25-Dihydroxycholecalciferol</span> Chemical compound

24,25-Dihydroxycholecalciferol, also known as 24,25-dihydroxyvitamin D3 and (24R)-hydroxycalcidiol (abbreviated as 24(R),25-(OH)2D3), is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3. Like vitamin D3 itself and calcifediol (25-hydroxyvitamin D3), it is inactive as a hormone both in vitro and in vivo. It was first identified in 1972 in the laboratory of Hector DeLuca and Michael F. Holick.

An endocrine bone disease is a bone disease associated with a disorder of the endocrine system. An example is osteitis fibrosa cystica.

<span class="mw-page-title-main">Alfacalcidol</span> Chemical compound

Alfacalcidol is an analogue of vitamin D used for supplementation in humans and as a poultry feed additive.

<span class="mw-page-title-main">Vitamin D</span> Group of fat-soluble secosteroids

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most significant compounds within this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).

<span class="mw-page-title-main">Michael F. Holick</span> American physician–scientist

Michael F. Holick is an American adult endocrinologist, specializing in vitamin D, such as the identification of both calcidiol, the major circulating form of vitamin D, and calcitriol, the active form of vitamin D. His work has been the basis for diagnostic tests and therapies for vitamin D-related diseases. He is a professor of medicine at the Boston University Medical Center and editor-in-chief of the journal Clinical Laboratory.

Chronic kidney disease–mineral and bone disorder (CKD–MBD) is one of the many complications associated with chronic kidney disease. It represents a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

References

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  3. ↑ Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.
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  5. ↑ Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster, archived from the original on 25 May 2020, retrieved 25 September 2015.
  6. 1 2 3 4 "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981". European Journal of Biochemistry. 124 (2): 223–227. May 1982. doi: 10.1111/j.1432-1033.1982.tb06581.x . PMID   7094913.
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  29. ↑ Ajibade DV, Dhawan P, Fechner AJ, Meyer MB, Pike JW, Christakos S (July 2010). "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". Endocrinology. 151 (7): 2974–2984. doi:10.1210/en.2010-0033. PMC   2903940 . PMID   20463051.
  30. ↑ Rodríguez-Ortiz ME, Rodríguez M (2015). "FGF23 as a calciotropic hormone". F1000Research. 4: 1472. doi: 10.12688/f1000research.7189.1 . PMC   4815615 . PMID   27081473.
  31. ↑ Adams JS, Hewison M (July 2012). "Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase". Archives of Biochemistry and Biophysics. 523 (1): 95–102. doi:10.1016/j.abb.2012.02.016. PMC   3361592 . PMID   22446158.
  32. 1 2 Mazzaferro S, Goldsmith D, Larsson TE, Massy ZA, Cozzolino M (March 2014). "Vitamin D metabolites and/or analogs: which D for which patient?". Current Vascular Pharmacology. 12 (2): 339–349. doi:10.2174/15701611113119990024. PMID   23713876.
  33. ↑ Brandi ML (September 2010). "Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes". Clinical Cases in Mineral and Bone Metabolism. 7 (3): 243–250. PMC   3213838 . PMID   22460535.
  34. ↑ Jones G, Prosser DE, Kaufmann M (January 2014). "Cytochrome P450-mediated metabolism of vitamin D". Journal of Lipid Research. 55 (1): 13–31. doi: 10.1194/jlr.R031534 . PMC   3927478 . PMID   23564710.
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  36. ↑ Holick MF, Schnoes HK, DeLuca HF (April 1971). "Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine". Proceedings of the National Academy of Sciences of the United States of America. 68 (4): 803–804. Bibcode:1971PNAS...68..803H. doi: 10.1073/pnas.68.4.803 . PMC   389047 . PMID   4323790.
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