Calcitriol is the active form of vitamin D, normally made in the kidney. A manufactured form is used to treat kidney disease with low blood calcium, hyperparathyroidism due to kidney disease, low blood calcium due to hypoparathyroidism, osteoporosis, osteomalacia, and familial hypophosphatemia. It is taken by mouth or by injection into a vein.
Excessive amount commonly results 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. Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines.
Calcitriol was approved for medical use in the United States in 1978. It is avaliable as a generic medication. A month supply in the United Kingdom costs the NHS about 9.70 £ as of 2019. In the United States the wholesale cost of this amount is about 27 USD. In 2016 it was the 231st most prescribed medication in the United States with more than 2 million prescriptions.
|Pronunciation||US: /ˌkælsɪˈtraɪɒl/; |
|Trade names||Rocaltrol, Calcijex, Decostriol, others|
|Synonyms||1,25-dihydroxycholecalciferol, 1alpha,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D3, 1α,25-(OH)2D3, 1,25(OH)2D|
|By mouth, IV|
|Elimination half-life||5–8 hours (adults), 27 hours (children)|
|Excretion||Faeces (50%), urine (16%)|
|Chemical and physical data|
|Molar mass||416.64 g/mol g·mol−1|
|3D model (JSmol)|
Calcitriol is prescribed for:
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.
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.
Calcitriol increases blood calcium levels ([Ca2+
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).
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.
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.
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 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. 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.
When the drug alfacalcidol is used, 25-hydroxylation in the liver will produce 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.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Calcitriol's lifespan in the body is measured in hours, unlike its precursor calcifediol whose lifespan 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 24-hydroxylase. Calcitroic acid is more soluble in water and is excreted in bile and urine.
Calcitriol usually refers specifically to 1,25-dihydroxycholecalciferol. Because cholecalciferol already has one hydroxyl group, only two (1,25) are further specified in this nomenclature, but there are three (1,3,25-triol), as indicated in when calcitriol is used. 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 (Roche), Calcijex (Abbott), Decostriol (Mibe, Jesalis), Vectical (Galderma), and Rolsical (Sun Pharma).
25-Hydroxyvitamin D3 1-alpha-hydroxylase (VD3 1A hydroxylase) also known as cytochrome p450 27B1 (CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.VD3 1A hydroxylase is located in the proximal tubule of the kidney and a variety of other tissues, including skin (keratinocytes), immune cells, and bone (osteoblasts). The enzyme catalyzes the hydroxylation of Calcifediol to calcitriol (the bioactive form of Vitamin D):
calcidiol + 2 reduced adrenodoxin + 2 H+ + O2 ⇌ calcitriol + 2 oxidized adrenodoxin + H2OAlfacalcidol
Alfacalcidol (or 1-hydroxycholecalciferol) is an analogue of vitamin D used for supplementation in humans and as a poultry feed additive.
Alfacalcidol has a weaker impact on calcium metabolism and parathyroid hormone levels than calcitriol, however alfacalcidol has significant effects on the immune system, including regulatory T cells. It is considered to be a more useful form of vitamin D supplementation, mostly due to much longer half-life and lower kidney load. It is the most commonly prescribed vitamin D metabolite for patients with end stage renal disease, given that impaired renal function alters the ability to carry out the second hydroxylation step required for the formation of the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3. Alfacalcidol is an active vitamin D3 metabolite, and therefore does not require the second hydroxylation step in the kidney.It was patented in 1971 and approved for medical use in 1978.CYP24A1
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 184.108.40.206)Calcifediol
Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D), is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase. Physicians worldwide measure this metabolite to determine a patient's vitamin D status. At a typical daily intake of vitamin D3, its full conversion to calcifediol takes approximately 7 days.Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation.Calcipotriol
Calcipotriol, also known as calcipotriene, is a synthetic derivative of calcitriol, a form of vitamin D. It is used in the treatment of psoriasis. It is safe for long-term application in psoriatic skin conditions.
It was patented in 1985 and approved for medical use in 1991. It is marketed under the trade name "Dovonex" in the United States, "Daivonex" outside North America, and "Psorcutan" in Germany.Calcitriol receptor
The calcitriol receptor, more commonly known as the vitamin D receptor (VDR) and also known as NR1I1 (nuclear receptor subfamily 1, group I, member 1), is a member of the nuclear receptor family of transcription factors. Calcitriol, the active form of vitamin D, binds to the VDR, which then forms a heterodimer with the retinoid-X receptor. This then binds to hormone response elements on DNA resulting in expression or transrepression of specific gene products. The VDR not only regulates transcriptional responses but also involved in microRNA-directed post transcriptional mechanisms. In humans, the vitamin D receptor is encoded by the VDR gene.Glucocorticoids are known to decrease expression of VDR, which is expressed in most tissues of the body and regulate intestinal transport of calcium, iron and other minerals.Calcitroic acid
Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3) is a major metabolite of 1α,25-dihydroxyvitamin D3 (calcitriol). Its formation is catalyzed by the enzyme CYP24A1, also called calcitriol 24-hydroxylase. It is thought to be the major route to inactivate vitamin D metabolites. Calcitroic acid is soluble in water and excreted in bile.
A recent review suggested that current knowledge of calcitroic acid is limited, and more studies are needed to identify its physiological role.In case where a higher concentration of this acid is used in vitro, studies determined that calcitroic acid binds to vitamin D receptor (VDR) and induces gene transcription.Calcium in biology
Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms and the cell. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of all muscle cell types, and in fertilization. Many enzymes require calcium ions as a cofactor, including several of the coagulation factors. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation.
Plasma calcium levels in mammals are tightly regulated, with bone acting as the major mineral storage site. Calcium ions, Ca2+, are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such as serum albumin. Parathyroid hormone secreted by the parathyroid gland regulates the resorption of Ca2+ from bone, reabsorption in the kidney back into circulation, and increases in the activation of vitamin D3 to calcitriol. Calcitriol, the active form of vitamin D3, promotes absorption of calcium from the intestines and bones. Calcitonin secreted from the parafollicular cells of the thyroid gland also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious.
Intracellular calcium is stored in organelles which repetitively release and then reaccumulate Ca2+ ions in response to specific cellular events: storage sites include mitochondria and the endoplasmic reticulum.Characteristic concentrations of calcium in model organisms are: in E. coli 3mM (bound), 100nM (free), in budding yeast 2mM (bound), in mammalian cell 10-100nM (free) and in blood plasma 2mM.Calcium metabolism
Calcium metabolism refers to the movements and regulation of calcium ions (Ca2+) in and out of various body compartments, such as the gastrointestinal tract, the blood plasma, the extracellular and intracellular fluids, and bone tissue. An important aspect of calcium metabolism is plasma calcium homeostasis, the regulation of calcium ions in the blood plasma within narrow limits. In this process, bone tissue acts as a calcium storage center for deposits and withdrawals as needed by the blood, via continual bone remodeling. Derangement of this mechanism leads to hypercalcemia or hypocalcemia, both of which can have consequences for health. The level of the calcium in humans' plasma is regulated by calcitonin and parathyroid hormone (PTH); calcitonin is released by the thyroid gland when its plasma level is above its set normal point (in order to lower calcium level); PTH is released by the parathyroid glands when calcium level falls below set point (in order to raise it).Cholecalciferol
Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of vitamin D which is made by the skin when exposed to sunlight; it is also found in some foods and can be taken as a dietary supplement. It is used to treat and prevent vitamin D deficiency and associated diseases, including rickets. It is also used for familial hypophosphatemia, hypoparathyroidism that is causing low blood calcium, and Fanconi syndrome. It is usually taken by mouth.Excessive doses can result in vomiting, constipation, weakness, and confusion. Other risks include kidney stones. Normal doses are safe in pregnancy. It may not be effective in people with severe kidney disease.Cholecalciferol is made in the skin following UVB light exposure. It is converted in the liver to calcifediol (25-hydroxyvitamin D) which is then converted in the kidney to calcitriol (1,25-dihydroxyvitamin D). One of its actions is to increase the uptake of calcium by the intestines. It is found in food such as some fish, cheese, and eggs. Certain foods such as milk have cholecalciferol added to them in some countries.Cholecalciferol was first described in 1936. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Cholecalciferol is available as a generic medication and over the counter.Eldecalcitol
Eldecalcitol is a drug used in Japan for the treatment of osteoporosis. It is an analog of vitamin D.
Osteoporosis is a common bone disease among the older generation, with an estimated prevalence of over 200 million people. This condition often results in bone fractures due to abnormally low bone mass density, and is a leading cause of disability, especially among developed countries with longer average life spans. Osteoporosis is more common in women than with men.Oxyphil cell (parathyroid)
In the parathyroid gland, the parathyroid oxyphil cell is larger and lighter staining than the parathyroid chief cell.These cells can be found in clusters in the center of the section and at the periphery. Oxyphil cells appear at the onset of puberty, but have no known function. With nuclear medicine scans, they selectively take up the Technetium-sestamibi complex radiotracer to allow delineation of glandular anatomy.
Oxyphil cells have been shown to express parathyroid-relevant genes found in the chief cells and have the potential to produce additional autocrine/paracrine factors, such as parathyroid hormone-related protein (PTHrP) and calcitriol. More work needs to be done to fully understand the functions of these cells and their secretions.Previtamin D3
Previtamin D3 is an intermediate in the production of cholecalciferol (vitamin D3). It is formed by the action of UV light, most specifically UVB light of wavelengths between 295 and 300 nm, acting on 7-dehydrocholesterol in the epidermal layers of the skin. It then undergoes spontaneous isomerization into cholecalciferol, the prohormone of the active form of vitamin D, calcitriol.Pseudohypoparathyroidism
Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is appropriately high (due to the low level of calcium in the blood). Its pathogenesis has been linked to dysfunctional G Proteins (in particular, Gs alpha subunit). The condition is extremely rare, with an estimated overall prevalence of 7.2/1,000,000 or approximately 1/140,000.Renal osteodystrophy
Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and renal failure.The traditional types of renal osteodystrophy have been defined on the basis of turnover and mineralization as follows: 1) mild, slight increase in turnover and normal mineralization; 2) osteitis fibrosa, increased turnover and normal mineralization; 3) osteomalacia, decreased turnover and abnormal mineralization; 4) adynamic, decreased turnover and acellularity; and, 5) mixed, increased turnover with abnormal mineralization. A Kidney Disease: Improving Global Outcomes report has suggested that bone biopsies in patients with CKD should be characterized by determining bone turnover, mineralization, and volume (TMV system).On the other hand, CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: 1) abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; 2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy); and 3) vascular or other soft-tissue calcification.Vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and multiple other biological effects. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol). Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements. Only a few foods contain vitamin D. The major natural source of the vitamin is synthesis of cholecalciferol in the skin from cholesterol through a chemical reaction that is dependent on sun exposure (specifically UVB radiation). Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.Vitamin D from the diet, or from skin synthesis, is biologically inactive. A protein enzyme must hydroxylate it to convert it to the active form. This is done in the liver and in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals exposed to sufficient sunlight, it is not an essential dietary factor, and so not technically a vitamin. Instead it could be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations. Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia). Vitamin D supplements are given to treat or to prevent osteomalacia and rickets, but the evidence for other health effects of vitamin D supplementation in the general population is inconsistent. The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people, and another concluding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is unneeded in these areas.Vitamin D-dependent calcium-binding protein
Vitamin D-dependent calcium binding proteins were discovered in the cytosolic fractions of chicken intestine, and later in mammalian intestine and kidney, by workers including Robert Wasserman of Cornell University.They bound calcium in the micromolar range and were greatly reduced in vitamin D-deficient animals. Expression could be induced by treating these animals with vitamin D metabolites such as calcitriol.
They were found to exist in two distinct sizes with a molecular weight of approximately 9 kDa and 28 kDa. They were renamed calbindin. Calbindin-D9k (S100G) is found in mammalian intestine and calbindin-D28k is in avian intestine and in mammalian kidney and other tissues.Vitamin D3 24-hydroxylase
Vitamin D3 24-hydroxylase (EC 220.127.116.11, CYP24A1) is an enzyme with systematic name calcitriol,NADPH:oxygen oxidoreductase (24-hydroxylating). This enzyme catalyses the following chemical reaction
Vitamin D3 24-hydroxylase is a heme-thiolate enzyme (P-450).X-linked hypophosphatemia
X-linked hypophosphatemia (XLH), is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. The prevalence of the disease is 1:20000. The leg deformity can be treated with Ilizarov frames and CAOS. It is also treated with medications including human growth hormone, calcitriol, and phosphate.