 Chemical Structure.png)
Calcitriol (RO215535, Topitriol; 1,25(OH)2D3) is an agonist of the vitamin D receptor (VDR) and the form of vitamin D that is metabolically and hormonally active. When calcitriol is converted, it produces metabolites that are more powerful and act faster than other vitamin D forms. Calcitriol regulates the differentiation, growth, and function of the cell immune system, which plays a major role in maintaining mineral and skeletal homeostasis. Studies conducted in vitro have revealed that calcitriol can inhibit the production of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in human peripheral blood cells (PBMC) stimulated by lipopolysaccharide (LPS) in a dose-dependent manner.
Physicochemical Properties
| Molecular Formula | C27H44O3 | |
| Molecular Weight | 416.64 | |
| Exact Mass | 416.329 | |
| Elemental Analysis | C, 77.84; H, 10.65; O, 11.52 | |
| CAS # | 32222-06-3 | |
| Related CAS # | (1S)-Calcitriol;61476-45-7;Calcitriol-d6;78782-99-7;Calcitriol-13C3;Calcitriol-d3;128723-16-0;Calcitriol Derivatives;2070009-24-2 | |
| PubChem CID | 5280453 | |
| Appearance | White to off-white solid powder | |
| Density | 1.1±0.1 g/cm3 | |
| Boiling Point | 565.0±50.0 °C at 760 mmHg | |
| Melting Point | 119-1210C | |
| Flash Point | 238.4±24.7 °C | |
| Vapour Pressure | 0.0±3.5 mmHg at 25°C | |
| Index of Refraction | 1.547 | |
| LogP | 6.12 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 30 | |
| Complexity | 688 | |
| Defined Atom Stereocenter Count | 6 | |
| SMILES | 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 |
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| InChi Key | GMRQFYUYWCNGIN-NKMMMXOESA-N | |
| InChi Code | 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 | |
| Chemical Name | (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 | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
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. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
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] |
| ln Vitro |
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] 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] |
| ln Vivo |
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). 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] |
| Enzyme Assay |
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]. 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] |
| Cell Assay |
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]. 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] |
| Animal Protocol |
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] 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] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion 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. 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. 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. In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours. 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. Upon intravenous administration, the volume of distribution of calcitriol was 0.49±0.14 L/kg in healthy male volunteers and 0.27±0.06 l/kg in uraemic male patients participating in a pharmacokinetic study. There is some evidence that calcitriol is transferred into human milk at low levels (ie, 2.2±0.1 pg/mL) in mothers. Calcitriol from maternal circulation may also enter the fetal circulation. The metabolic clearance rate was 23.5±4.34 ml/min in healthy male volunteers and 10.1±1.35 ml/min in male patients with uraemia. In the pediatric patients undergoing peritoneal dialysis receiving dose of 10.2 ng/kg (SD 5.5 ng/kg) for 2 months, the clearance rate was 15.3 mL/hr/kg. Many vitamin D analogs are readily absorbed from the GI tract following oral administration if fat absorption is normal. The presence of bile is required for absorption of ergocalciferol and the extent of GI absorption may be decreased in patients with hepatic, biliary, or GI disease (e.g., Crohn's disease, Whipple's disease, sprue). 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, principally in the small intestine. Although some evidence suggested that intestinal absorption of vitamin D may be decreased in geriatric adults, other evidence did not show clinically important age-related alterations in GI absorption of the vitamin in therapeutic doses. It currently is not known whether aging alters the GI absorption of physiologic amounts of vitamin D. /Vitamin D analogs/ After oral administration of calcitriol, there is about a 2-hour lag-time before calcium absorption in the GI tract increases. Maximal hypercalcemic effect occurs in about 10 hours, and the duration of action of calcitriol is 3-5 days. Time to peak serum concentration: Oral: Approximately 3 to 6 hours. The primary route of excretion of vitamin D is the bile; only a small percentage of an administered dose is found in urine. /Vitamin D/ For more Absorption, Distribution and Excretion (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (10 total), please visit the HSDB record page. Metabolism / Metabolites Metabolism of calcitriol involves two pathways. 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. Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-a-hydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. 1,25-Dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol appear to be metabolized to their respective trihydroxy metabolites (i.e., 1,24,25-trihydroxycholecalciferol, 1,24,25-trihydroxyergocalciferol) and to other compounds. The principal metabolite excreted in urine is calcitroic acid, which is more water soluble. Although all the metabolites of cholecalciferol and ergocalciferol have not been identified, hepatic microsomal enzymes may be involved in degrading metabolites of ergocalciferol and cholecalciferol. Calcitriol /(1,25-dihydroxy-vitamin D)/ is hydroxylated to 1,24,25-(OH)3-D by a renal hydroxylase that is induced by calcitriol and suppressed by those factors that stimulate the 25-OHD-1-alpha-hydroxylase. This enzyme also hydroxylates 25-OHD to form 24,25-(OH)2D. Both 24-hydroxylated compounds are less active than calcitriol and presumably represent metabolites destined for excretion. Side chain oxidation of calcitriol also occurs. To evaluate the relation between daily and fasting urinary calcium excretion and serum 1,25-dihydroxyvitamin D (II) concentrations, 6 healthy men were studied during control and during chronic oral calcitrol (I) administration (0.6, 1.2, or 1.8 nmols every 6 hours for 6-12 days) while they ate normal and low calcium diets (19.2 or 4.2 mmols Ca/day). Daily urinary calcium excretion was directly related to serum II concentrations, but increased more while subjects ate the normal calcium diet than when eating the low calcium diet. During I and ingestion of the low calcium diet, daily urinary calcium excretion averaged 7.32 mmole/day, exceeding the dietary calcium intake. Fasting urinary calcium/creatinine exceeded 0.34 mmol/mmol (the upper limit of normal) on either diet. When serum II concentrations are elevated, a high fasting urinary calcium/creatinine or high daily urinary calcium excretion, even on a low calcium diet, is insufficient criteria for the documentation of a renal calcium leak. For more Metabolism/Metabolites (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (7 total), please visit the HSDB record page. 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. The lactone appears to be the major metabolite circulating in humans. Route of Elimination: Enterohepatic recycling and biliary excretion of calcitriol occur. 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. Half Life: 5-8 hours Biological Half-Life After administration of single oral doses, the elimination half life was 5-8 hours. Plasma half-life: 3 to 6 hours. Calcitriol (1,25-Dihydroxyvitamin D3) has an oral bioavailability of ~42% in humans [1] Calcitriol (1,25-Dihydroxyvitamin D3) reaches peak plasma concentrations (Cmax) of 45 pg/mL at Tmax = 4 h after oral administration of 0.5 μg in healthy volunteers [1] The plasma elimination half-life (t1/2) of Calcitriol (1,25-Dihydroxyvitamin D3) in humans is 5–8 hours [1] Calcitriol (1,25-Dihydroxyvitamin D3) is primarily metabolized in the liver and kidneys via hydroxylation, with metabolites excreted in bile and urine [1] |
| Toxicity/Toxicokinetics |
Toxicity Summary 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. Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Calcitriol is the normal physiologically active form of vitamin D, 1,25-dihydroxyvitamin D. Several women with hypocalcemia have successfully breastfed during breastfeeding, with sometimes fluctuating serum calcium levels. Limited data indicate that its use in nursing mothers in appropriately adjusted doses does not affect the breastfed infant. If the mother requires calcitriol, it is not a reason to discontinue breastfeeding. Calcitriol and calcium dosage requirements are usually reduced during lactation in women with hypoparathyroidism. ◉ Effects in Breastfed Infants A woman with hypoparathyroidism breastfed her infant from week 1 to week 32 postpartum while taking calcitriol. The dose was initially 0.5 mcg daily, but was decreased to 0.25 mcg daily after 8 weeks. The infant thrived during breastfeeding and had normal serum calcium levels at 1 and 3 weeks and 3 months of age. A woman breastfed infants after two pregnancies while taking calcitriol in doses of 0.75 and 1 mcg daily. There were no reports of adverse reactions. A woman breastfed her newborn infant for 9 days while taking calcitriol 0.5 mcg three times daily. Calcitriol was stopped at that time because of hypercalcemia, but restarted at 40 days postpartum in low doses that were gradually increased until the prepregnancy dosage of 1.5 mcg daily was reached just before weaning at 12.5 months postpartum. A woman with discoid lupus was taking calcitriol 0.25 mcg every 2 days and several other medications concurrently. Her infant was breastfed for 12 months and followed up at 15 months of age. No adverse effects were reported during breastfeeding and the infant was growing and developing normally at 15 months of age. A nursing mother with autosomal dominant hypoparathyroidism type 1 was treated with teriparatide for 8 months postpartum then calcitriol 0.5 mcg twice daily was substituted. She breastfed her infant exclusively for 6 months then with supplementation to 1 year. Her infant had no change in serum calcium when maternal calcitriol was begun. The mother began weaning at 11 months and at 1 year of age weaning was complete. Growth and development were normal at 1.5 years of age. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Calcitriol is approximately 99.9% bound in blood, mostly by an alpha-globulin vitamin D binding protein. Toxicity Data LD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg. Interactions Corticosteroids counteract the effects of vitamin D analogs. /Vitamin D analogs/ Concurrent administration of thiazide diuretics and pharmacologic doses of vitamin D analogs in patients with hypoparathyroidism may result in hypercalcemia which may be transient and self-limited or may require discontinuance of vitamin D analogs. Thiazide-induced hypercalcemia in hypoparathyroid patients is probably caused by increased release of calcium from bone. /Vitamin D analogs/ Excessive use of mineral oil may interfere with intestinal absorption of vitamin D analogs. /Vitamin D analogs/ Orlistat may result in decreased GI absorption of fat-soluble vitamins such as vitamin D analogs. At least 2 hours should elapse between (before or after) any orlistat dose and vitamin D analog administration ... . /Vitamin D analogs/ For more Interactions (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (8 total), please visit the HSDB record page. Calcitriol (1,25-Dihydroxyvitamin D3) induced 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] Chronic administration of Calcitriol (1,25-Dihydroxyvitamin D3) at doses > 1 μg/kg/day in mice caused mild renal calcification [4] |
| References |
[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 > |
| Additional Infomation |
Therapeutic Uses Bone Density Conservation Agents; Calcium Channel Agonist; Vitamins Calcium Channel Agonists; Dermatologic Agents Medication: Calcium regulator; vitamin (antirachitic) Therapeutic doses of specific vitamin D analogs are used in the treatment of chronic hypocalcemia, hypophosphatemia, rickets, and osteodystrophy associated with various medical conditions including chronic renal failure, familial hypophosphatemia, and hypoparathyroidism (postsurgical or idiopathic, or pseudohypoparathyroidism). Some analogs have been found to reduct elevated parathyroid hormone concentrations in patients with renal osteodystrophy associated with hyperparathyroidism. Theoretically, any of the vitamin D analogs may be used for the above conditions, However, because of their pharmacologic properties, some may be more useful in certain situations than others. Alfacalcidol, calcitriol, and dihydrotachysterol are usually preferred in patients with renal failure since these patients have impaired ability to synthesize calcitriol from cholecalciferol and ergocalciferol; therefore, the response is more predictable. In addition, their shorter half-lives may make toxicity easier to manage (hypercalcemia reverses more quickly). Ergocalciferol may not be the preferred agent in the treatment of familial hypophosphatemia or hypoparathyroidism because the large doses needed are associated with a risk of overdose and hypercalcemia; dihydrotachysterol and calcitriol may be preferred. /Included in US product labeling/ For more Therapeutic Uses (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (6 total), please visit the HSDB record page. Drug Warnings ... When serum alkaline phosphate decreases, serum calcium rises. Metastatic calcification, decrease in renal function, and increased serum phosphate levels are possible consequences. POTENTIAL ADVERSE EFFECTS ON FETUS: Teratogenic in animals at high doses (4-15x recommended human dose). In humans, maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D, suppression of parathyroid function or a syndrome of elfin facies, mental retardation, and congenital supravalvular aortic stenosis. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: No known problems at recommended daily allowance. /Cholecalciferol from table II/ Doses of vitamin D analogs that do not exceed the physiologic requirement are usually nontoxic. However, some infants and patients with sarcoidosis or hypoparathyroidism may have increased sensitivity to vitamin D analogs. /Vitamin D analogs/ Decreased renal function without hypercalcemia has also been reported in patients with hypoparathyroidism after long-term vitamin D analog therapy. Before therapy with vitamin D analogs is initiated, serum phosphate concentrations must be controlled. To avoid ectopic calcification, the serum calcium (in mg/dL) times phosphorus (in mg/dL) should not be allowed to exceed 70. Because administration of vitamin D analogs may increase phosphate absorption, patients with renal failure may require adjustment in the dosage of aluminum-containing antacids used to decrease phosphate absorption. /Vitamin D analogs/ For more Drug Warnings (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (13 total), please visit the HSDB record page. 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. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal (GI) tissues, bones, and kidneys. 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. 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. 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. 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. 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. 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. 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. Calcitriol (1,25-Dihydroxyvitamin D3) is the active hormonal form of vitamin D3, synthesized from 25-hydroxyvitamin D3 via renal 1α-hydroxylase [1] Calcitriol (1,25-Dihydroxyvitamin D3) exerts biological effects by binding to VDR, forming a heterodimer with RXR, and regulating 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 suppressing 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) modulates steroid hormone metabolism by regulating aromatase activity, potentially affecting estrogen synthesis [5] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. 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. 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. 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. 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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4002 mL | 12.0008 mL | 24.0015 mL | |
| 5 mM | 0.4800 mL | 2.4002 mL | 4.8003 mL | |
| 10 mM | 0.2400 mL | 1.2001 mL | 2.4002 mL |