Absorption, Distribution and Excretion
Many vitamin D analogs are readily absorbed from the gastrointestinal tract after oral administration if fat absorption is normal. Ergocalciferol absorption requires the presence of bile, 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 is currently unclear whether aging affects the gastrointestinal absorption of physiological doses of vitamin D. /Vitamin D Analogs/ After oral administration of calcitriol, gastrointestinal calcium absorption increases after approximately 2 hours. 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 fraction of the administered dose is excreted in the urine. /Vitamin D/
For more complete data on the absorption, distribution, and excretion of 1,25-dihydroxycholecalciferol (10 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Calcitriol is the active form of vitamin D3 (cholecalciferol). The supply of natural or endogenous vitamin D in the human body depends primarily on the conversion of 7-dehydrocholesterol to vitamin D3 in the skin by ultraviolet radiation. 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 (calciferol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, a reaction activated by renal 25-hydroxyvitamin D3-1α-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 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 renal hydroxylase. This hydroxylase is 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 have lower activity 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 a long-term oral administration of calcitriol(I) (0.6, 1.2, or 1.8 nmol every 6 hours for 6–12 days), while simultaneously consuming 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 (the upper limit of normal). When serum β2 concentrations are elevated, even on a low-calcium diet, an elevated fasting urinary calcium/creatinine ratio or elevated daily urinary calcium excretion is not sufficient to diagnose renal calcium leakage. For more complete metabolite/metabolite data on 1,25-dihydroxycholecalciferol (7 metabolites), please visit the HSDB record page.

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Biological half-life
Plasma half-life: 3 to 6 hours.

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Calcitriol is the normal physiologically active form of vitamin D, 1,25-dihydroxyvitamin D. Some women with hypocalcemia successfully breastfeed, but serum calcium levels may fluctuate. Limited data suggest that calcitriol use by breastfeeding women with appropriately adjusted dosages does not affect breastfed infants. If the mother needs to take calcitriol, this is not a reason to stop breastfeeding. For women with hypoparathyroidism, the dosage of calcitriol and calcium usually needs to be 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 infants grew and developed well during breastfeeding, with normal serum calcium levels at 1 week, 3 weeks, and 3 months of age. One woman took 0.75 mcg and 1 mcg of calcitriol daily during two pregnancies and breastfed. No adverse reactions were reported. One woman started breastfeeding her newborn 9 days after birth and took 0.5 mcg of calcitriol three times daily. Due to hypercalcemia, calcitriol was discontinued at that time but resumed 40 days postpartum, with the dose gradually increased until it returned to 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, concurrently taking several other medications. Her infant was breastfed for 12 months and was followed up at 15 months of age. No adverse reactions were reported during breastfeeding, and the infant's growth and development were normal at 15 months of age. A breastfeeding 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 after the mother started calcitriol. The mother began weaning the infant at 11 months of age and completed weaning at 1 year of age. The infant's 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.

[1]. (2000) The in vitro effect of calcitriol on parathyroid cell proliferation and apoptosis. J.Am.Soc.Nephrol. 11 1865. Beer and Myrthue (2004).

[2]. Calcitriol in cancer treatment: from the lab to the clinic. Mol.Cancer Ther. 3 373.

[3]. Nijenhuis et al (2006) The novel vitamin D analog ZK191784 as an intestine-specific vitamin D antagonist. FASEB J. 20 1589.

[4]. Krishnan AV, Swami S, Feldman D.Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: Importance of mammary CYP27B1 for treatment and prevention.J Steroid Biochem Mol Biol. 2012 Aug 23.

[5]. Alkharfy KM, Al-Daghri NM, Yakout SM, Ahmed M.Calcitriol Attenuates Weight-Related Systemic Inflammation and Ultrastructural Changes of the Liver in a Rodent Model.Basic Clin Pharmacol Toxicol. 2012 Aug 21.

Mechanism of Action
Ergocalciferol and docecalciferol (1-hydroxyergocalciferol); cholecalciferol and calcidiol (25-hydroxycholecalciferol); and the active forms of dihydrotachysterol (1,25-dihydroxyergocalciferol; 1,25-dihydroxycholecalciferol [calcitriol]; and 25-hydroxydihydrotachysterol, respectively) regulate serum calcium concentration along with parathyroid hormone and calcitonin. Calcidiol is active itself, in addition to being converted to the active form of 1,25-dihydroxycholecalciferol. Calcitriol (active vitamin D) enhances calcium absorption throughout the small intestine, particularly the duodenum and jejunum. Calcitriol also enhances phosphorus absorption throughout the small intestine, especially the jejunum and ileum. The active forms of ergocalciferol, docecalciferol, and cholecalciferol may have a negative feedback effect on parathyroid hormone (PTH) production. Calcitriol's mechanism of action in the gut appears to be similar to that of steroid hormones such as estrogen acting on target tissues. …Chicken intestinal cells contain a 3.7S protein in their cytosol that specifically and with high affinity binds to calcitriol. Formation of a complex with this receptor facilitates calcitriol transport to nuclear chromatin. …Calcitriol stimulates the synthesis of RNA and at least two proteins in the intestinal mucosa: alkaline phosphatase and calcium-binding protein. …Some studies have suggested that this calcium-binding protein is involved in calcium transport. However, it has been reported that calcitriol-induced intestinal phosphate transport stimulation precedes calcium transport; therefore, the vitamin's primary role may be phosphate transport rather than calcium transport. This study investigated the effects of 1,25-dihydroxyvitamin D3 (I) on the human promyelocytic leukemia cell line HL-60. I induced HL-60 cells to differentiate into monocytes and multinucleated macrophage-like cells. Phenotypic changes were observed within 24 hours and reached a plateau after 72–96 hours of incubation. These changes are metabolite-specific, including substrate adhesion, acquisition of mature monocyte morphology, a 4- to 6-fold increase in lysozyme synthesis and secretion, and an increased proportion of α-naphthaleneacetate monocyte-associated cell surface antigen. Treated HL-60 cells acquired the ability to bind and degrade the bone matrix, two essential functional characteristics of osteoclasts and related bone resorption cells. Clearly, vitamin D3 enhances bone resorption and osteoclastogenesis in vivo by promoting precursor cell differentiation. For more complete data on the mechanisms of action of 1,25-dihydroxycholecalciferol (one of six), please visit the HSDB record page.

C27H44O3

416.63646

422.367

78782-99-7

Calcitriol;32222-06-3

2524

White to off-white solid powder

111-115 °C

5.704

3

3

6

30

688

0

GMRQFYUYWCNGIN-UHFFFAOYSA-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

5-[2-[1-(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: 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)

DMSO : ~50 mg/mL (~118.30 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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