Calcitriol: Difference between revisions

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{{Short description|Active form of vitamin D}}

{{Infobox drug

| caption          =

<!-- Clinical data -->

| pronounce = {{IPAc-en|US|ˌ|k|æ|l|s|ᵻ|ˈ|t|r|aɪ|ɒ|l}}; <br /> {{IPAc-en|UK|k|æ|l|ˈ|s|ɪ|t|r|i|ɒ|l}}

| ATC_supplemental =  {{ATC|D05|AX03}}

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| legal_AU = S4

| legal_status      = <!-- For countries not listed above -->

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| bioavailability =   

| excretion = Faeces (50%), urine (16%)

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| CAS_number_Ref = {{cascite|correct|??}}

| synonyms        = 1,25-dihydroxycholecalciferol, 1alpha,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D₃, 1α,25-(OH)₂D₃, 1,25(OH)₂D

<!-- Chemical and physical data -->

| IUPAC_name = (1''R'',3''S'')-5-[2-[(1''R'',3a''R'',7a''S'')-1-[(2''R'')-6-hydroxy-6-methyl-heptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1''H''- inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol

}}

<!-- Definition and physiology -->

'''Calcitriol''' is the active form of [[vitamin D]], normally made in the [[kidney]]. It is also known as '''1,25-dihydroxycholecalciferol'''. It is a [[hormone]] which binds to and activates the [[vitamin D receptor]] in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood [[Calcium in biology|calcium]] (Ca²⁺) mainly by increasing the uptake of calcium from the [[intestines]].

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It can be given as a medication for the treatment of [[hypocalcemia|low blood calcium]] and [[hyperparathyroidism]] due to [[kidney disease]], low blood calcium due to [[hypoparathyroidism]], [[osteoporosis]], [[osteomalacia]], and [[familial hypophosphatemia]], and can be taken by mouth or by [[intravenous|injection into a vein]]. Excessive amounts or intake can result in weakness, headache, nausea, constipation, [[urinary tract infections]], and abdominal pain. Serious side effects may include [[high blood calcium]] and [[anaphylaxis]]. Regular blood tests are recommended after the medication is started and when the dose is changed.

<!-- History and culture -->

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. It is available as a [[generic medication]]. In 2021, it was the 258th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions. It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].

==Medical use==

Calcitriol is prescribed for:

* Prevention of [[corticosteroid-induced osteoporosis]]

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

==Adverse effects==

The main [[adverse drug reaction]] associated with calcitriol therapy is [[hypercalcemia]] – early symptoms include: [[nausea]], [[vomiting]], [[constipation]], [[anorexia (symptom)|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 [[elimination half-life|half-life]].

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]].

Other conditions producing similar findings including:

* Miscellaneous; mycobacterium avium, leprosy, lipoid pneumonia, cat scratch fever, berylliosis

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.

== Mechanism of action ==

Calcitriol increases blood calcium levels ([{{chem|Ca|2+}}]) by:

* 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]].

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 {{chem|Ca|2+}}. 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).

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 (biochemistry)|ligand]]-receptor complex translocates to the [[cell nucleus]], where it acts as a [[transcription factor]] promoting the expression of a gene encoding a [[Vitamin D-dependent calcium-binding protein|calcium binding protein]]. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium ({{chem|Ca|2+}}) from the intestine across the [[intestinal mucosa]] into the blood. Alternative, ''non-genomic'' pathways may be mediated through either [[PDIA3]] or VDR.

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.

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

== Biosynthesis and its regulation ==

[[Image:Calcitriol-Synthesis.png|thumb|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|25-hydroxyvitamin D₃ 1-alpha-hydroxylase]], a [[mitochondria]]l [[oxygenase]] and an [[enzyme]] which catalyzes the [[hydroxylation]] of [[Calcifediol|25-hydroxycholecalciferol (calcifediol)]] in the 1-alpha position.

The activity of this enzyme is stimulated by PTH. This is an important control point in [[Calcium metabolism|Ca²⁺ homeostasis]]. 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. 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.

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

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.

===Interactive pathway map===

{{VitaminDSynthesis WP1531|highlight=Calcitriol}}

===Metabolism===

The halflife of calcitriol in the body is measured in hours, unlike its precursor calcifediol, whose halflife is measured in weeks. Calcitriol is inactivated by further hydroxylation to form 1,24,25-trihydroxyvitamin D, [[calcitroic acid]]. This occurs through the action of the CYP24A1 [[CYP24A1|24-hydroxylase]]. 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]], and also by [[Anthony W. Norman|Tony Norman]] and colleagues.

== 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.

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). 1α,25-Dihydroxyergocalciferol (ercalcitriol) should be used for the vitamin D₂ product. 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. In clinical use, the differences are unlikely to have major importance.

Calcitriol is marketed as a pharmaceutical for medical use under various trade names including Rocaltrol ([[Hoffman-La Roche|Roche]]), Calcijex ([[Abbott Laboratories|Abbott]]), Decostriol (Mibe, Jesalis), Vectical ([[Galderma]]), and Rolsical ([[Sun Pharmaceutical|Sun Pharma]]).

{{Hormones}}

{{Vitamins}}

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{{二次利用|date=20 March 2024}}

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