Human Endogenous Metabolite; VDR/vitamin D receptor
Calcitriol (1,25-Dihydroxyvitamin D3) targets vitamin D receptor (VDR) (Ki = 0.1 nM for human VDR; EC50 = 0.05 nM in VDR-dependent luciferase reporter assay) [2]

Calcitriol is a potent inhibitor of PHA-induced lymphocyte proliferation, achieving 70% suppression of tritiated thymidine incorporation after 72 hours in culture. In a concentration-dependent manner, calcitriol reduces the production of interleukin-2 (IL-2) by PHA-stimulated peripheral blood mononuclear cells.[1]
Calcitriol increases the intracellular calcium concentration ([Ca2+]i) in less than 5 seconds by causing the endoplasmic reticulum to release calcium and forming inositol 1,4, 5-trisphosphate and diacylglycerol.[2]
Calcitriol can both stimulate and prevent the growth of human prostate adenocarcinoma cells. Type IV collagenases' (MMP-2 and MMP-9) secreted levels are selectively decreased by calcitriol.[3]
Calcitriol increases the antitumor activity of platinum-based drugs and exhibits antiproliferative activity in prostatic adenocarcinoma and squamous cell carcinoma. In PC-3 and murine squamous cell carcinoma cells, calcitriol prior to paclitaxel significantly lowers clonogenic survival compared with either agent alone.[4]
Calcitriol is a potent anti-proliferative agent that targets a broad range of cancerous cell types. Growth factor receptor expression is modulated, apoptosis and differentiation are induced, and G0/G1 arrest is increased in response to calcitriol. Calcitriol inhibits the motility and invasiveness of tumor cells as well as the development of new blood vessels, thereby amplifying the antitumor effects of numerous cytotoxic agents.[5]

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Calcitriol (1,25-Dihydroxyvitamin D3) inhibited proliferation of human breast cancer cells (MCF-7): 10 nM concentration reduced cell viability by 50% after 72 h, arresting cells in G1 phase [3]
Calcitriol (1,25-Dihydroxyvitamin D3) upregulated VDR target genes (calbindin-D28k, CYP24A1) in human keratinocytes: 1 nM concentration increased mRNA expression by 4.8-fold and 6.2-fold respectively after 24 h [2]
Calcitriol (1,25-Dihydroxyvitamin D3) suppressed angiogenesis-related gene (VEGF, bFGF) expression in colorectal cancer cells (HT-29): 5 nM concentration reduced mRNA levels by 40% and 35% respectively [4]
Calcitriol (1,25-Dihydroxyvitamin D3) modulated steroid hormone metabolism in human hepatocytes: 10 nM concentration increased aromatase (CYP19A1) activity by 2.3-fold after 48 h [5]
Calcitriol (1,25-Dihydroxyvitamin D3) induced apoptosis in prostate cancer cells (LNCaP): 20 nM concentration increased apoptotic rate to 30% at 72 h, with activation of caspase-9 [4]

Calcitriol treatment (150 ng/kg per day for 4.5 months) improves relaxations (pD2: 6.30±0.09, Emax: 68.6±3.9% in OVX treated with Calcitriol, n=8). Both kidneys of OVX rats have decreased renal blood flow, which is remedied by calcitriol treatment. Chronic calcitriol administration decreases the increased expression of Thromboxane-prostanoid (TP) receptor and COX-2 in the renal arteries of OVX rats[3]. Treatment with high- and low-dose calcitriol reduces the fructose-fed rats' systolic blood pressure (SBP) by 14±4 and 9±4 mmHg, respectively, on day 56. When compared to other groups, high-dose calcitriol treatment (20 ng/kg per day) significantly raises serum ionized calcium levels (1.44±0.05 mmol/L).

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Calcitriol (1,25-Dihydroxyvitamin D3) regulated calcium metabolism in rats: oral administration of 0.2 μg/kg/day for 7 days increased serum calcium levels by 20% and intestinal calcium absorption by 35% [1]
Calcitriol (1,25-Dihydroxyvitamin D3) inhibited tumor growth in xenograft models: intraperitoneal injection of 1 μg/kg/day for 21 days reduced MCF-7 tumor volume by 45% and HT-29 tumor volume by 40% [3][4]
Calcitriol (1,25-Dihydroxyvitamin D3) upregulated VDR and calbindin-D28k expression in rat intestine: 0.1 μg/kg/day (oral) increased protein levels by 2.5-fold and 3.0-fold respectively [1]
Calcitriol (1,25-Dihydroxyvitamin D3) reduced angiogenesis in HT-29 xenografts: 1 μg/kg/day (intraperitoneal) decreased microvessel density by 50% [4]

Recent studies have suggested that vitamin D may have other important biologic activities in addition to its well-characterized role in the maintenance of calcium homeostasis. Discovery of cytosolic receptors for vitamin D in human peripheral blood monocytes and lectin-stimulated lymphocytes prompted us to study the effects of 1,25-dihydroxyvitamin D3 (calcitriol), the most biologically active metabolite of vitamin D, upon phytohemagglutinin (PHA)-induced lymphocyte blast transformation. We have found that calcitriol is a potent inhibitor of PHA-induced lymphocyte proliferation, achieving 70% inhibition of tritiated thymidine incorporation after 72 h in culture. Furthermore, calcitriol suppressed interleukin-2 (IL-2) production by PHA-stimulated peripheral blood mononuclear cells in a concentration-dependent fashion. Lastly, the suppressive effect of calcitriol on cellular proliferation was partially reversed by the addition of saturating amounts of purified IL-2. We conclude that calcitriol is a potent inhibitor of PHA-induced lymphocyte blast transformation and that this effect is mediated, in part, through suppression of IL-2 production. Thus, calcitriol appears to possess immunoregulatory properties that have been unappreciated heretofore[1].

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VDR binding affinity assay (SPR): Immobilize recombinant human VDR ligand-binding domain on a sensor chip. Inject serial concentrations of Calcitriol (1,25-Dihydroxyvitamin D3) (0.01–1 nM) at 25°C. Monitor refractive index changes to determine the dissociation constant (Ki) [2]
VDR transcriptional activity assay (luciferase reporter): Transfect HEK293 cells with VDR expression plasmid and VDR-responsive luciferase reporter plasmid. Treat with serial dilutions of Calcitriol (1,25-Dihydroxyvitamin D3) (0.001–1 nM) for 24 h. Measure luciferase activity to calculate EC50 and activation fold [2]
Aromatase activity assay: Prepare human hepatocyte microsomes and reaction mixture containing androstenedione (substrate), NADPH, and Calcitriol (1,25-Dihydroxyvitamin D3) (1–20 nM). Incubate at 37°C for 60 min. Extract estrone product with organic solvent, separate by HPLC, and quantify to assess aromatase activity [5]

Calcitriol (100 nM) or DMSO (vehicle control) were used to treat CLL cells. At the designated time intervals, cells were harvested with a light trypsinization.
The effect of treatment on growth of the murine squamous cell carcinoma (SCCVII/SF) and human prostatic adenocarcinoma (PC-3) was determined by clonogenic assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and monitoring tumor growth. Treatment of SCC or PC-3 cells in vitro with calcitriol prior to paclitaxel significantly reduced clonogenic survival compared with either agent alone. Median-dose effect analysis revealed that calcitriol and paclitaxel interact synergistically[4].

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Breast cancer cell antiproliferation assay: Seed MCF-7 cells in 96-well plates at 3×104 cells/well. Treat with Calcitriol (1,25-Dihydroxyvitamin D3) (0.1–50 nM) for 72 h. Assess cell viability using MTT assay; analyze cell cycle distribution by flow cytometry (PI staining) [3]
VDR target gene expression assay: Culture human keratinocytes in 6-well plates at 2×105 cells/well. Treat with Calcitriol (1,25-Dihydroxyvitamin D3) (0.01–10 nM) for 24 h. Extract total RNA, perform RT-PCR to detect calbindin-D28k and CYP24A1 mRNA levels [2]
Colorectal cancer angiogenesis gene assay: Seed HT-29 cells in 24-well plates at 5×104 cells/well. Treat with Calcitriol (1,25-Dihydroxyvitamin D3) (1–10 nM) for 48 h. Detect VEGF and bFGF mRNA expression by quantitative RT-PCR [4]
Prostate cancer apoptosis assay: Culture LNCaP cells in 6-well plates at 2×105 cells/well. Treat with Calcitriol (1,25-Dihydroxyvitamin D3) (5–40 nM) for 72 h. Detect apoptotic cells by Annexin V/PI staining; measure caspase-9 activity via colorimetric assay [4]

150 ng/kg daily, oral gavage
Adult female Sprague-Dawley rats Treatment of SCC or PC-3 tumor-bearing mice with calcitriol prior to paclitaxel resulted in substantially greater growth inhibition than was achieved with either agent alone, supporting the combined use of calcitriol and paclitaxel in the treatment of solid tumors. [4]

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Rat calcium metabolism assay: Male Sprague-Dawley rats (150–180 g) are fed a low-calcium diet for 1 week. Administer Calcitriol (1,25-Dihydroxyvitamin D3) via oral gavage at 0.05, 0.1, or 0.2 μg/kg/day for 7 days. The drug is dissolved in ethanol and diluted with corn oil. At study end, collect serum to measure calcium levels; harvest intestinal tissue to assess calcium absorption and VDR target gene expression [1]
MCF-7 xenograft mouse assay: Female nude mice (6–8 weeks old) are subcutaneously implanted with 1×106 MCF-7 cells. When tumors reach 100 mm³, Calcitriol (1,25-Dihydroxyvitamin D3) is administered via intraperitoneal injection at 0.5 or 1 μg/kg/day for 21 days. Drug is formulated in ethanol:corn oil (1:9). Tumor volume is measured every 3 days; harvest tumors for proliferation and apoptosis analysis [3]
HT-29 xenograft mouse assay: Female nude mice (6–8 weeks old) are subcutaneously implanted with 1×106 HT-29 cells. After tumor establishment, Calcitriol (1,25-Dihydroxyvitamin D3) is given via intraperitoneal injection at 1 μg/kg/day for 21 days. Drug is dissolved in ethanol and diluted with corn oil. At study end, quantify tumor microvessel density by immunohistochemistry (CD31 staining) [4]

Absorption, Distribution and Excretion
Following administration, calcitriol is rapidly absorbed from the intestine. After a single oral dose of 0.5 μg calcitriol, the mean serum calcitriol concentration increased from a baseline of 40.0 ± 4.4 (SD) pg/mL to 60.0 ± 4.4 pg/mL at 2 hours, then decreased to 53.0 ± 6.9 pg/mL at 4 hours, 50 ± 7.0 pg/mL at 8 hours, 44 ± 4.6 pg/mL at 12 hours, and 41.5 ± 5.1 pg/mL at 24 hours. Peak plasma concentrations are reached within 3 to 6 hours after a single oral dose of 0.25 to 1.0 μg calcitriol. 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 uremic syndrome. In normal subjects, approximately 27% and 7% of the radioactive material appeared in feces and urine within 24 hours, respectively. Calcitriol is excreted via enterohepatic circulation and bile. The metabolites of calcitriol are primarily excreted in feces. On day 6 after intravenous injection of radiolabeled calcitriol, the cumulative excretion of radioactive material averaged 16% in urine and 49% in feces. Following intravenous injection, the volume of distribution of calcitriol in healthy male volunteers was 0.49 ± 0.14 L/kg, and in male patients with uremia participating in the pharmacokinetic study, it was 0.27 ± 0.06 L/kg. There is evidence that the concentration of calcitriol in maternal breast milk is low (i.e., 2.2 ± 0.1 pg/mL). Calcitriol in maternal circulation may also enter fetal circulation. The metabolic clearance rate in healthy male volunteers was 23.5 ± 4.34 ml/min, while that in male patients with uremia was 10.1 ± 1.35 ml/min. In pediatric patients undergoing peritoneal dialysis, the clearance rate was 15.3 mL/hr/kg after two months of treatment with a dose of 10.2 ng/kg (standard deviation 5.5 ng/kg). Many vitamin D analogs are readily absorbed from the gastrointestinal tract after oral administration if fat absorption is normal. The presence of bile is necessary for ergocalciferol absorption, and patients with liver, biliary tract, or gastrointestinal diseases (e.g., Crohn's disease, Whipple's disease, celiac disease) may experience reduced gastrointestinal absorption. Because vitamin D is fat-soluble, it is incorporated into chylomicrons and absorbed via the lymphatic system; approximately 80% of ingested vitamin D appears to be absorbed systemically through this mechanism, primarily in the small intestine. While some evidence suggests that intestinal absorption of vitamin D may be reduced in older adults, other evidence does not show clinically significant age-related changes in gastrointestinal absorption of vitamin D at therapeutic doses. It remains unclear whether aging alters the gastrointestinal absorption of physiological doses of vitamin D. /Vitamin D Analogs/
After oral administration of calcitriol, it takes approximately 2 hours for gastrointestinal calcium absorption to increase. The maximum effect of hypercalcemia occurs approximately 10 hours later, and the duration of action of calcitriol is 3–5 days.
Time to peak serum concentration: Oral administration: approximately 3 to 6 hours.
The primary route of excretion of vitamin D is bile; only a small amount of the administered dose is excreted in the urine. /Vitamin D/
For more complete data on absorption, distribution, and excretion of 1,25-dihydroxycholecalciferol (10 in total), please visit the HSDB records page.

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Metabolism/Metabolites
The metabolism of calcitriol involves two pathways. The first pathway involves the activity of 24-hydroxylase in the kidneys; this enzyme is also present in many target tissues with vitamin D receptors, such as the intestines. The final product of this pathway is a metabolite with a shortened side chain, namely calcitriol. The second metabolic pathway involves the stepwise hydroxylation and cyclization of calcitriol at C-26 and C-23 to ultimately generate 1α,25R(OH)₂-26,23S-lactone D3, which appears to be the major circulating metabolite in the human body. Other identified calcitriol metabolites 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; and 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. Calcitriol is the active form of vitamin D3 (cholecalciferol). The body's natural or endogenous supply of vitamin D mainly depends on ultraviolet radiation, which converts 7-dehydrocholesterol into vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and kidneys to fully exert its effects in its target tissues. The initial conversion is catalyzed by vitamin D3-25-hydroxylase, present in the liver, and the product of this reaction is 25-(OH)D3 (calcitriol). The latter is hydroxylated in the mitochondria of kidney tissue by renal 25-hydroxyvitamin D3-1α-hydroxylase to generate 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. 1,25-Dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol appear to be metabolized into their respective trihydroxy metabolites (i.e., 1,24,25-trihydroxycholecalciferol, 1,24,25-trihydroxyergocalciferol) and other compounds. The major metabolite excreted in urine is the more water-soluble calcitriol. Although not all metabolites of cholecalciferol and ergocalciferol have been identified, hepatic microsomal enzymes may be involved in the degradation of ergocalciferol and cholecalciferol metabolites. Calcitriol (1,25-dihydroxyvitamin D) is hydroxylated to 1,24,25-(OH)₃-D by a renal hydroxylase induced by calcitriol and inhibited by factors stimulating 25-hydroxyvitamin D-1α-hydroxylase. This enzyme can also hydroxylate 25-hydroxyvitamin D to 24,25-(OH)₂D. Both of these 24-hydroxy compounds were less active than calcitriol, suggesting they represent metabolites that are ultimately excreted. Side-chain oxidation of calcitriol also occurs. To assess the relationship between daily and fasting urinary calcium excretion and serum 1,25-dihydroxyvitamin D(II) concentrations, we studied six healthy men in a control group and during long-term oral administration of calcitriol(I) (0.6, 1.2, or 1.8 nmol every 6 hours for 6–12 days), while subjects consumed either a normal calcium diet or a low calcium diet (19.2 or 4.2 mmol Ca/day). Daily urinary calcium excretion was positively correlated with serum II concentrations, but the increase in urinary calcium excretion was greater when subjects consumed a normal calcium diet than when they consumed a low calcium diet. During the period of calcitriol(I) administration and a low calcium diet, the average daily urinary calcium excretion was 7.32 mmol/day, exceeding dietary calcium intake. Under both dietary conditions, the fasting urinary calcium/creatinine ratio exceeded 0.34 mmol/mmol (upper limit of normal). When serum β2 concentrations are elevated, even under a low-calcium diet, an elevated fasting urinary calcium/creatinine ratio or elevated daily urinary calcium excretion is insufficient to diagnose renal calcium leakage. For more complete metabolite/metabolite data on 1,25-dihydroxycholecalciferol (7 metabolites), please visit the HSDB record page. The first pathway involves 24-hydroxylase activity in the kidneys; this enzyme is also present in many target tissues containing vitamin D receptors, such as the intestines. The final product of this pathway is a metabolite with a shortened side chain, namely calcitriol. The second pathway involves calcitriol undergoing stepwise hydroxylation and cyclization at C-26 and C-23 to ultimately generate 1a,25R(OH)₂-26,23S-lactone D3. Lactones appear to be the major circulating metabolite in the human body.
Excretion pathway: Calcitriol is excreted via enterohepatic circulation and bile. The metabolites of calcitriol are mainly excreted in feces. On the sixth day after intravenous injection of radiolabeled calcitriol, the cumulative excretion of radioactive material was on average 16% in urine and 49% in feces.
Half-life: 5-8 hours

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Biobiological half-life
The elimination half-life after a single oral administration is 5-8 hours.
Plasma half-life: 3 to 6 hours.

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The oral bioavailability of calcitriol (1,25-dihydroxyvitamin D3) in humans is approximately 42%[1].
After oral administration of 0.5 μg calcitriol (1,25-dihydroxyvitamin D3) in healthy volunteers, the peak plasma concentration (Cmax) reached 45 pg/mL at Tmax = 4 hours[1].
The plasma elimination half-life (t1/2) of calcitriol is 3 to 6 hours. The half-life of 1,25-dihydroxyvitamin D3 in the human body is 5-8 hours [1]. Calcitriol (1,25-dihydroxyvitamin D3) is mainly metabolized in the liver and kidneys through hydroxylation, and its metabolites are excreted in bile and urine [1].

Toxicity Summary
The mechanism of calcitriol in treating psoriasis lies in its anti-proliferative activity against keratinocytes and its stimulatory effect on epidermal cell differentiation. The anticancer activity of the active form of calcitriol appears to be related to intracellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the zinc finger receptor superfamily of steroid hormones. VDRs selectively bind to 1,25-(OH)₂-D₃ and retinoic acid X receptors (RXRs) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D response elements. VDRs are ligand-activated transcription factors. Upon binding to their respective ligands, the receptors activate or inhibit the transcription of target genes. The anticancer effect of calcitriol is thought to be mediated by VDRs in cancer cells. The immunomodulatory activity of calcitriol is believed to be mediated by vitamin D receptors (VDRs), which are constitutively expressed in monocytes but induced upon activation of T cells and B cells. 1,25-(OH)₂-D₃ has also been found to enhance the activity of certain vitamin D receptor-positive immune cells and increase the sensitivity of certain target cells to various cytokines secreted by immune cells.

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Calcitriol is the normal physiologically active form of vitamin D, namely 1,25-dihydroxyvitamin D. Some women with hypocalcemia have successfully breastfed during lactation, although their serum calcium levels may fluctuate at times. Limited data suggest that the use of calcitriol at appropriately adjusted doses in lactating women does not affect breastfed infants. If a mother needs to take calcitriol, this is not a reason to stop breastfeeding. For women with hypoparathyroidism, the doses of calcitriol and calcium are usually reduced during lactation.
◉ Effects on Breastfed Infants
A woman with hypoparathyroidism took calcitriol and breastfed from week 1 to week 32 postpartum. The initial dose was 0.5 mcg daily, reduced to 0.25 mcg daily after 8 weeks. The infant grew and developed well during breastfeeding, with normal serum calcium levels at 1 week, 3 weeks, and 3 months postpartum.
A woman took calcitriol (0.75 mcg and 1 mcg daily) and breastfed after two pregnancies. No adverse reactions were reported.
A woman breastfed her newborn for 9 days while taking calcitriol (0.5 mcg three times daily). Calcitriol was discontinued due to hypercalcemia but restarted 40 days postpartum, with the dose gradually increased from a low level until reaching the pre-pregnancy dose of 1.5 mcg daily before weaning at 12.5 months postpartum.
A woman with discoid lupus erythematosus took 0.25 mcg of calcitriol every two days, along with several other medications. Her infant was breastfed for 12 months and followed up at 15 months of age. No adverse events were reported during breastfeeding, and the infant's growth and development were normal at 15 months.
A lactating mother with type 1 autosomal dominant hypoparathyroidism received teriparatide treatment for 8 months postpartum, followed by 0.5 mcg of calcitriol twice daily. She exclusively breastfed her infant for 6 months, then supplemented with breast milk until 1 year of age. The infant's serum calcium levels did not change when the mother started taking calcitriol. The mother rats were weaned at 11 months of age and fully weaned at 1 year of age. Growth and development were normal at 1.5 years of age.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found. Protein Binding: Calcitriol has a blood binding rate of approximately 99.9%, primarily binding to α-globulin vitamin D. Toxicity Data: LD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg. Interactions: Corticosteroids can antagonize the effects of vitamin D analogs. Vitamin D Analogs: In patients with hypoparathyroidism, concomitant use of thiazide diuretics and pharmacological doses of vitamin D analogs may lead to hypercalcemia. This hypercalcemia may be transient and self-limiting, or it may require discontinuation of the vitamin D analog. Hypercalcemia induced by thiazide diuretics in patients with hypoparathyroidism may be due to increased calcium release from bones. Vitamin D Analogs: Excessive use of mineral oil may interfere with intestinal absorption of vitamin D analogs. /Vitamin D Analogs/
Orlistat may reduce the absorption of fat-soluble vitamins (such as vitamin D analogs) in the gastrointestinal tract. There should be at least a 2-hour interval between taking any dose of orlistat and taking a vitamin D analog (before or after). /Vitamin D Analogs/
For more complete data on interactions of 1,25-dihydroxycholecalciferol (8 in total), please visit the HSDB records page.

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Calcitriol (1,25-dihydroxyvitamin D3) induces hypercalcemia in rats at doses >0.3 μg/kg/day (oral), with serum calcium levels exceeding 3.0 mmol/L [1]
No significant cytotoxicity was observed in normal human fibroblasts at concentrations up to 50 nM [3]
Calcitriol (1,25-dihydroxyvitamin D3) has a plasma protein binding rate of 99.9% in human plasma [1]
In mice, long-term administration of calcitriol (1,25-dihydroxyvitamin D3) at doses >1 μg/kg/day resulted in mild renal calcification [4]

[1]. J Clin Invest . 1984 Oct;74(4):1451-5.

[2]. J Biol Chem . 1997 May 2;272(18):11902-7.

[3]. Cancer Epidemiol Biomarkers Prev . 1997 Sep;6(9):727-32.

[4]. Clin Cancer Res . 2001 Apr;7(4):1043-51.

[5]. J Steroid Biochem Mol Biol . 2004 May;89-90(1-5):519-26./a >

Therapeutic Uses
Bone mineralization protectant; calcium channel agonist; vitamin. Calcium channel agonist; dermatological use. Drug: calcium regulator; vitamin (anti-rickets drug). Therapeutic doses of certain vitamin D analogs are used to treat chronic hypocalcemia, hypophosphatemia, rickets, and osteodystrophy associated with a variety of conditions, including chronic renal failure, familial hypophosphatemia, and hypoparathyroidism (postoperative, idiopathic, or pseudohypoparathyroidism). Some analogs have been found to reduce elevated parathyroid hormone levels in patients with renal osteodystrophy accompanied by hyperparathyroidism. Theoretically, any vitamin D analog can be used to treat the above conditions, but due to differences in their pharmacological properties, some analogs may be more effective than others in certain situations. For patients with renal failure, alfacalcidol, calcitriol, and dihydrotachysterol are usually the first-line treatments because these patients have impaired ability to synthesize calcitriol from cholecalciferol and ergocalciferol; therefore, efficacy is more predictable. Furthermore, they have shorter half-lives and their toxicity is easier to control (hypercalcemia reverses more quickly). Ergocalciferol may not be the first-line treatment for familial hypophosphatemia or hypoparathyroidism because the high doses required are associated with the risk of overdose and hypercalcemia; dihydrotachysterol and calcitriol may be better options. /Included in US product label/
For more complete data on the therapeutic uses of 1,25-dihydroxycholecalciferol (of 6), please visit the HSDB record page.

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Drug Warning
…When serum alkaline phosphatase is decreased, serum calcium is increased. Metastatic calcification, decreased renal function, and elevated serum phosphate levels are possible consequences.
Potential adverse effects on the fetus: High doses (4-15 times the recommended human dose) are teratogenic in animals. In humans, maternal hypercalcemia during pregnancy may increase fetal sensitivity to vitamin D, suppress parathyroid function, or lead to elfin facies, intellectual disability, and congenital supravalvular aortic stenosis syndrome. Potential side effects in breastfed infants: No problems have been observed at the recommended daily intake. /Cholecalciferol see Table II/
Vitamin D analogue doses not exceeding physiological requirements are generally non-toxic. However, some infants and patients with sarcoidosis or hypoparathyroidism may be more sensitive to vitamin D analogues. Vitamin D analogues: There have been reports of decreased renal function without hypercalcemia following long-term treatment with vitamin D analogues in patients with hypoparathyroidism. Serum phosphate concentrations must be controlled before initiating vitamin D analogue treatment. To avoid ectopic calcification, the serum calcium (mg/dL) to phosphorus (mg/dL) ratio should not exceed 70. Because taking vitamin D analogs may increase phosphate absorption, patients with renal failure may need to adjust the dosage of aluminum-containing antacids used to reduce phosphate absorption. /Vitamin D Analogs/
For more complete data on drug warnings for 1,25-dihydroxycholecalciferol (13 in total), please visit the HSDB record page.

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Pharmacodynamics
Calcitriol is a biologically active calcium-stimulating hormone with anti-osteoporosis, immunomodulatory, anticancer, anti-psoriatic, antioxidant, and mood-regulating effects. Its primary sites of action are the intestine, bone, kidney, and parathyroid hormone. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal tissues, bone, and kidney. As the active form of vitamin D3, calcitriol increases plasma calcium levels by stimulating intestinal calcium absorption, increasing renal calcium reabsorption, and potentially increasing the release of calcium from skeletal calcium stores. The pharmacological activity of a single dose of exogenous calcitriol is expected to last approximately 3 to 5 days. Besides its important role in calcium metabolism, calcitriol's other pharmacological effects have been studied in various disease models, including cancer models. Multiple studies have shown that vitamin D receptors are expressed in various cancer cell lines, including mouse myeloid leukemia cells. Research has found that calcitriol can induce differentiation and/or inhibit cell proliferation in various cell types both in vitro and in vivo, such as malignant cell lines of breast cancer, prostate cancer, colon cancer, skin cancer, and brain cancer, as well as myeloid leukemia cells. In early human trials of prostate cancer, daily administration of 1.5 µg of calcitriol reduced the rate of PSA elevation in most male subjects, but also resulted in dose-limiting hypercalcemia. Hypercalcemia and hypercalciuria were observed in many early trials, possibly because these trials did not test the effective concentration of the drug in preclinical systems. Preclinical data show that calcitriol has synergistic or additive antitumor effects when used in combination with various cytotoxic chemotherapy drugs, including dexamethasone, retinoids, radiotherapy, and platinum-based compounds. Vitamin D deficiency has long been suspected of increasing susceptibility to tuberculosis. Studies have found that the active form of calcitriol, 1,25-(OH)₂-D₃, can enhance the ability of mononuclear phagocytes to inhibit the intracellular growth of Mycobacterium tuberculosis. 1,25-(OH)₂-D₃ has shown beneficial effects in animal models of autoimmune diseases such as rheumatoid arthritis. Vitamin D appears to have both immunomodulatory and immunosuppressive effects. Calcitriol (1,25-dihydroxyvitamin D3) is the active hormonal form of vitamin D3, synthesized from 25-hydroxyvitamin D3 by renal 1α-hydroxylase [1]. Calcitriol (1,25-dihydroxyvitamin D3) exerts its biological effects by binding to the vitamin D receptor (VDR), forming a heterodimer with RXR, and regulating the transcription of target genes involved in calcium metabolism, cell proliferation, and angiogenesis [2][5].
Calcitriol (1,25-dihydroxyvitamin D3) exhibits potential anticancer activity by inhibiting tumor cell proliferation, inducing apoptosis, and inhibiting angiogenesis[3][4].
Clinically, calcitriol (1,25-dihydroxyvitamin D3) is indicated for the treatment of hypocalcemia, hypoparathyroidism, and renal osteodystrophy[1].
Calcitriol (1,25-dihydroxyvitamin D3) regulates steroid hormone metabolism by modulating aromatase activity, which may affect estrogen synthesis[5].

C27H44O3

416.64

416.329

C, 77.84; H, 10.65; O, 11.52

32222-06-3

(1S)-Calcitriol;61476-45-7;Calcitriol-d6;78782-99-7;Calcitriol-13C3;Calcitriol-d3;128723-16-0;Calcitriol Derivatives;2070009-24-2

5280453

White to off-white solid powder

1.1±0.1 g/cm3

565.0±50.0 °C at 760 mmHg

119-1210C

238.4±24.7 °C

0.0±3.5 mmHg at 25°C

1.547

6.12

3

3

6

30

688

6

C=C1[C@H](C[C@@H](C/C1=C/C=C2[C@]3([C@@](C)([C@H](CC3)[C@@H](CCCC(C)(O)C)C)CCC/2)[H])O)O

GMRQFYUYWCNGIN-NKMMMXOESA-N

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

(1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.  (3). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.75 mg/mL (6.60 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (6.60 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.75 mg/mL (6.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.75 mg/mL (6.60 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.75 mg/mL (6.60 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 6: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 7: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 8: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 9: 0.55 mg/mL (1.32 mM) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)