General
Preferred name
CALCITRIOL
Synonyms
1,25-dihydroxyvitamin D3 ()
CPD000466393 ()
Calcitriol D6 ()
Calcitriol (Rocaltrol) ()
Calcitriol-d6 ()
Calcijex ()
1ALPHA,25-DIHYDROXYVITAMIN D3 ()
1,25-HYDROXYLATED VITAMIN D ()
1ALPHA,25-DIHYDROXYCHOLECALCIFEROL ()
1,25-DIHYDROXY VITAMIN D3 ()
Dihydroxyvitamin D 3 ()
RO-215535 ()
RO-21-5535 ()
VECTICAL ()
SILKIS ()
RO 21-5535 ()
Rocaltrol ()
P&D ID
PD003123
CAS
32222-06-3
1000873-74-4
78782-99-7
Tags
available
drug
Approved by
FDA
First approval
1978
Drug indication
Basal cell carcinoma
Congenital alopecia
Drug Status
approved
nutraceutical
Max Phase
4.0
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
ROE
In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours [FDA Label]. Calcitriol undergoes enterohepatic recycling and biliary excretion. The metabolites of calcitriol are excreted primarily in feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces [FDA Label].
TOXICITY
LD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg [MSDS]. Symptoms of calcitriol toxicity mirrors the early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia [L5653]. Early signs include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. Late signs are characterized by polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis [L5653].
HALF-LIFE
After administration of single oral doses, the elimination half life was 5-8 hours [FDA Label].
MOA
The mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)2-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)2-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells.; ; A study suggests that calcitriol plays an immunoregulatry role by suppressing the aryl hydrocarbon receptor (AhR) expression in human Th9, a pro-inflammatory CD4 T cell subset [A175747]. This suppression subsequently leads to repressed expression of BATF, a transcription factor essential for Th9 [A175747]. Calcitriol has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes.
TOXICITY
LD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg [MSDS].; ; Symptoms of calcitriol toxicity mirrors the early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia [L5653]. Early signs include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. Late signs are characterized by polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis [L5653].
METABOLISM
Metabolism of calcitriol involves two pathways [FDA Label]. The first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3, which appears to be the major metabolite circulating in humans.; ; Ohter identified metabolites of calcitriol include 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxo-D3; 1α, 25R,26(OH)3-23-oxo-D3 and 1α, (OH)24,25,26,27-tetranor-COOH-D3 [FDA Label].
DESCRIPTION
Vitamin D receptor agonist. Calcitrol is the active form of vitamin D found in the body.
(GtoPdb)
PHARMACODYNAMICS
Calcitriol is a biologically active calcitrophic hormone with anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Its main sites of action are the intestine, bone, kidney and parathyroid hormone [FDA Label]. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal (GI) tissues, bones, and kidneys [A3366]. As an active form of vitamin D3, calcitriol elevates the plasma levels of calcium by stimulating intestinal calcium uptake, increasing reabsorption of calcium by the kidneys, and possibly increasing the release of calcium from skeletal stores. The duration of pharmacologic activity of a single dose of exogenous calcitriol is expected to be about 3 to 5 days [FDA Label]. In addition to its important role in calcium metabolism, other pharmacological effects of calcitriol have been studied in various conditions including cancer models. Various studies demonstrated expression of vitamin D receptors in cancer cell lines, including mouse myeloid leukemia cells [A3366]. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation _in vitro_ and _in vivo_ in many cell types, such as malignant cell lines carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others [A3367]. In early human prostate cancer trials, administration of 1.5 µg/d calcitriol in male participants resulted in a reduction in the rate of PSA rise in most participants, however it was coincided with dose-limiting hypercalcemia in most participants [A3366]. Hypercalcemia and hypercalcuria were evident in numerous initial trials, and this may be due to these trials not testing the drug at concentrations that are active in preclinical systems [A3367]. Findings from preclinical data show an additive or synergistic antineoplastic action of calcitriol when combined with agents including dexamethasone, retinoids, and radiation, as well as several cytotoxic chemotherapy drugs such as platinum compounds [A3367]. Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of calcitriol, 1,25-(OH)2-D3, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of Mycobacterium tuberculosis. 1,25-(OH)2-D3 has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.
ABSORPTION
Upon administration, calcitriol is rapidly absorbed from the intestines. When a single oral dose of 0.5 mcg of calcitriol was administered, the mean serum concentrations of calcitriol rose from a baseline value of 40.0±4.4 (SD) pg/mL to 60.0±4.4 pg/mL at 2 hours, and declined to 53.0±6.9 at 4 hours, 50±7.0 at 8 hours, 44±4.6 at 12 hours and 41.5±5.1 at 24 hours [FDA Label]. Following administration of single doses of 0.25 to 1.0 mcg of calcitriol, the peak plasma concentrations were reached within 3 to 6 hours [FDA Label]. In a pharmacokinetic study, the oral bioavailability was 70.6±5.8% in healthy male volunteers and 72.2±4.8% in male patients with uraemia [A175726].
MOA
The mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)2-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)2-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells. A study suggests that calcitriol plays an immunoregulatry role by suppressing the aryl hydrocarbon receptor (AhR) expression in human Th9, a pro-inflammatory CD4 T cell subset [A175747]. This suppression subsequently leads to repressed expression of BATF, a transcription factor essential for Th9 [A175747]. Calcitriol has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes.
METABOLISM
Metabolism of calcitriol involves two pathways [FDA Label]. The first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3, which appears to be the major metabolite circulating in humans. Ohter identified metabolites of calcitriol include 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxo-D3; 1α, 25R,26(OH)3-23-oxo-D3 and 1α, (OH)24,25,26,27-tetranor-COOH-D3 [FDA Label].
PHARMACODYNAMICS
Calcitriol is a biologically active calcitrophic hormone with anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Its main sites of action are the intestine, bone, kidney and parathyroid hormone [FDA Label]. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal (GI) tissues, bones, and kidneys [A3366]. As an active form of vitamin D3, calcitriol elevates the plasma levels of calcium by stimulating intestinal calcium uptake, increasing reabsorption of calcium by the kidneys, and possibly increasing the release of calcium from skeletal stores. The duration of pharmacologic activity of a single dose of exogenous calcitriol is expected to be about 3 to 5 days [FDA Label]. ; ; In addition to its important role in calcium metabolism, other pharmacological effects of calcitriol have been studied in various conditions including cancer models. Various studies demonstrated expression of vitamin D receptors in cancer cell lines, including mouse myeloid leukemia cells [A3366]. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation _in vitro_ and _in vivo_ in many cell types, such as malignant cell lines carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others [A3367]. In early human prostate cancer trials, administration of 1.5 µg/d calcitriol in male participants resulted in a reduction in the rate of PSA rise in most participants, however it was coincided with dose-limiting hypercalcemia in most participants [A3366]. Hypercalcemia and hypercalcuria were evident in numerous initial trials, and this may be due to these trials not testing the drug at concentrations that are active in preclinical systems [A3367]. Findings from preclinical data show an additive or synergistic antineoplastic action of calcitriol when combined with agents including dexamethasone, retinoids, and radiation, as well as several cytotoxic chemotherapy drugs such as platinum compounds [A3367]. ; ; Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of calcitriol, 1,25-(OH)2-D3, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of Mycobacterium tuberculosis. 1,25-(OH)2-D3 has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.
PRICE
172
DESCRIPTION
Calcitriol (1,25-Dihydroxyvitamin D3) is a metabolite of vitamin D and a vitamin D receptor (VDR) agonist (IC50=0.4 nM). Calcitriol increases intestinal absorption of calcium and phosphorus, and increases bone resorption with parathyroid hormone.
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
17
Organisms
1
Compound Sets
27
AdooQ Bioactive Compound Library
Bioprocess diversity set
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2017/18
Concise Guide to Pharmacology 2019/20
Concise Guide to Pharmacology 2021/22
Concise Guide to Pharmacology 2023/24
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
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DrugMAP Approved Drugs
EUbOPEN Chemogenomics Library
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
Mcule NIBR MoA Box Subset
MedChem Express Bioactive Compound Library
NCATS Inxight Approved Drugs
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
NURSA ligand set
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
69
Molecular Weight
416.33
Hydrogen Bond Acceptors
3
Hydrogen Bond Donors
3
Rotatable Bonds
6
Ring Count
3
Aromatic Ring Count
0
cLogP
5.7
TPSA
60.69
Fraction CSP3
0.78
Chiral centers
6.0
Largest ring
6.0
QED
0.52
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
VD/VDR
VDR
Drug Metabolite
Endogenous Metabolite
Biological process
Resipration, oxidative phosphorylation, & mitochondrial targeting
Pathway
Vitamin D Related
Metabolic Enzyme/Protease
Vitamin D Related/Nuclear Receptor
MOA
Vitamin inhibitor
CYP27B1 metabolite
vitamin D receptor agonist
Member status
member
Indication
hypocalcemia, hypoparathyroidism, osteoporosis
Disease Area
endocrinology, orthopedics
Recommended Cell Concentration
1 uM
Source data
