Calcitriol

416.64

416.64

250-963-8

DTXSID5022722

Colorless, crystalline solid|White crystalline powder

2942000000

60.7

5.1

Solid

1.1±0.1 g/cm3

113 °C

565°C at 760 mmHg

14 °C

1.547

H2O: Insoluble

2-8°C

1.2X10-12 mm Hg at 25 deg C (est)

Oral-Rat  LD50 0.62  mg/kg; Oral-Mouse LD50: 1.35 mg/kg

Flammable, spicy and irritating smoke emitted from the fire

D25 +48° (methanol)

Henry's Law constant = 3.1X10-7 atm cu-m/mol at 25 °C (est)

Air and light sensitive|Hydroxyl radical reaction rate constant = 3.1X10-10 cu cm/molecule-second at 25 °C (est)

I

6.1(a)

UN 2811 6.1/PG 1

3

26/27/28-63-36/37/38-20/21/22-11

36/37/39-45-36-26-16-7

FZ4645000

T+,Xn,F

Treasury is ventilated, low temperature and dry; store and transport separately from food

Air and Light Sensitive

P210-P280-P302 + P352 + P312-P304 + P340 + P312-P370 + P378-P403 + P235

H225-H301 + H311 + H331-H370

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

A REVIEW ON THE 1,25-DIHYDROXYVITAMIN D3 [1,25-(OH)2D3] BINDING PROTEINS IN EEL (ANGUILLA ANGUILLA) TISSUES AND IN HUMAN BREAST CANCER[FREAKE HC ET AL; STUDIES WITH THE 1,25-(OH)2D3 BINDING PROTEIN; CLIN ENDOCRINOL CALCIUM METAB: 79 (1982)]

|Danger|H300 (100%): Fatal if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P262, P264, P270, P271, P280, P281, P284, P301+P310, P302+P350, P304+P340, P308+P313, P310, P320, P321, P322, P330, P361, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 91 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

highly toxic

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.

1,25-Dihydroxycholecalciferol's production and use for the management of hypocalcemia in patients undergoing chronic renal dialysis(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that 1,25-dihydroxycholecalciferol is expected to be immobile in soil(SRC). Volatilization of 1,25-dihydroxycholecalciferol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.1X10-7 atm-cu m/mole(SRC), using a fragment constant estimation method(3). 1,25-Dihydroxycholecalciferol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-12 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2006).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that 1,25-dihydroxycholecalciferol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.1X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 9600(SRC), from an estimated log Kow of 7.6(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Biodegradation data were not available(SRC, 2006).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,25-dihydroxycholecalciferol, which has an estimated vapor pressure of 1.2X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 1,25-dihydroxycholecalciferol may be removed from the air by wet or dry deposition(SRC). 1,25-Dihydroxycholecalciferol does absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

1,25-Dihydroxycholecalciferol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). 1,25-Dihydroxycholecalciferol does absorb at wavelengths >290 nm(2) and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 9600 was calculated for 1,25-dihydroxycholecalciferol(SRC), using an estimated log Kow of 7.6(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 1,25-dihydroxycholecalciferol can be estimated to be 1.1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1,25-dihydroxycholecalciferol is expected to be immobile in soil.

The Henry's Law constant for 1,25-dihydroxycholecalciferol is estimated as 3.1X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 1,25-dihydroxycholecalciferol is expected to be nonvolatile from moist soil or water surfaces(2). 1,25-Dihydroxycholecalciferol is expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-12 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to 1,25-dihydroxycholecalciferol were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to 1,25-dihydroxycholecalciferol may occur through inhalation and dermal contact with this compound at workplaces where 1,25-dihydroxycholecalciferol is produced or used. Exposure to 1,25-dihydroxycholecalciferol among the general population may be limited to those administered the drug Calcijex. (SRC)

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.

... 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.

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.

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.

Plasma half-life: 3 to 6 hours.

Ergocalciferol and doxercalciferol (1-hydroxyergocalciferol); cholecalciferol and calcifediol (25-hydroxycholecalciferol); and dihydrotachysterol in their activated forms (1,25-dihydroxyergocalciferol; 1,25-dihydroxycholecalciferol [calcitriol]; and 25-hydroxydihydrotachysterol; respectively), along with parathyroid hormone and calcitonin, regulate serum calcium concentrations; in addition to conversion to the active 1,25-dihydroxycholecalciferol, calcifediol also has intrinsic activity.|Calcitriol (activated vitamin D) enhances the efficiency of intestinal calcium absorption along the entire small intestine, but principally in the duodenum and jejunum. Calcitriol also enhances phosphorus absorption along the entire small intestine, but principally in the jejunum and ileum. The activated forms of ergocalciferol, doxercalciferol, and cholecalciferol may have a negative feedback effect on parathyroid hormone (PTH) production.|Calcitriol appears to act in intestine in manner that is analogous to the way steroid hormones such as estrogens act on target tissues. ... Cytosol of chicken intestinal cells contains a 3.7 S protein that binds calcitriol specifically and with high affinity. Formation of complex with this receptor facilitates transfer of calcitriol to nuclear chromatin. ... Calcitriol stimulates synthesis of RNA and at least two proteins in intestinal mucosa, alkaline phosphatase and a calcium-binding protein. ... It was proposed that the calcium-binding protein is involved in transport of calcium. ... /However/, it has been reported that calcitriol-induced stimulation of intestinal transport of phosphate precedes that of calcium, and it is possible that primary effect of the vitamin is on phosphate rather than calcium transport.|The effects of 1,25-dihydroxyvitamin D3 (I) on the human promyelocytic leukemia cell line HL-60 were investigated. I induces the differentiation of HL-60 into mono- and multinucleated macrophage-like cells. Phenotypic change is evident within 24 hours and reaches a plateau at 72-96 hours of incubation. The changes are metabolite-specific and include adherence to substrate, acquisition of the morphological features of mature monocytes, a 4 to 6-fold enhancement in lysozyme synthesis and secretion, increase in the fraction of alpha-naphthyl acetate monocyte-associated cell surface antigens. Treated HL-60 cells acquire the capacity to bind and degrade bone matrix, 2 of the essential functional characteristics of osteoclasts and related bone-resorbing cells. Evidently, vitamin D3 enhances bone resorption and osteoclastogenesis in vivo by promoting the differentiation of precursor cells.|For more Mechanism of Action (Complete) data for 1,25-DIHYDROXYCHOLECALCIFEROL (6 total), please visit the HSDB record page.

The treatment of acute accidental overdosage of Calcijex (calcitriol injection) should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and low calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patients' underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium-free dialysate has also been reported.|Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis: General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcijex (calcitriol injection) therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcijex therapy may be reinstituted at a dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

/SIGNS AND SYMPTOMS/ Patients should be informed of the dangers and symptoms of vitamin D intoxication. Early symptoms of hypercalcemia may include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, abdominal cramps, constipation, diarrhea, vertigo, tinnitus, ataxia, exanthema, hypotonia (in infants), muscle pain, bone pain, and irritability. Later and sometimes more serious consequences of hypercalcemia may include rhinorrhea, pruritus, decreased libido, nephrocalcinosis, impairment of renal function (resulting in polyuria, nocturia, polydipsia, hyposthenuria, and proteinuria), osteoporosis in adults, decreased growth in children, weight loss, anemia, calcific conjunctivitis, photophobia, metastatic calcification, pancreatitis, generalized vascular calcification, and seizures. Rarely, patients may develop hypertension or overt psychosis. Urinary calcium, phosphate, and albumin; BUN; and serum cholesterol, AST (SGOT), and ALT (SGPT) concentrations may increase. Serum alkaline phosphatase concentrations may decrease. Serum electrolyte imbalances along with mild acidosis may result in cardiac arrhythmias. /Vitamin D/|/SIGNS AND SYMPTOMS/ Vitamin D toxicity may be manifested in the fetus. There is a relationship between excess maternal vitamin D intake or extreme sensitivity and nonfamilial congenital supravalvular aortic stenosis. In infants, this anomaly is often associated with other stigmata of hypercalcemia. Maternal hypercalcemia also may result in suppression of parathyroid function in the newborn, with resultant hypocalcemia, tetany, and seizures. /Vitamin D/|/SIGNS AND SYMPTOMS/ The initial signs and symptoms of vitamin D toxicity are those associated with hypercalcemia. ... Hypercalcemia with hypervitaminosis D is due generally to very high circulating levels or 25-OHD (25-hydroxycholecalciferol), and plasma concentrations of PTH (parathyroid hormone) and calcitriol are typically but not uniformly suppressed. /Vitamin D/|/CASE REPORTS/ A 19-year-old patient with severe osteomalacia and secondary hyperparathyroidism had response to treatment with calcitriol that was critically dependent on the calcium in his diet. Patient was given sandocal (calcium lactate gluconate, combination, citric acid), which provided 40 mmol calcium daily. Plasma calcium concentration rose, plasma alkaline phosphatase, immunoreactive parathyroid hormone, and hydroxyproline concentrations fell, and symptoms abated. After 46 weeks of calcium supplements, skeletal X-rays showed loss of subperiosteal erosions and healing of epiphyseal abnormalities, but increased osteosclerosis. A repeat bone biopsy showed osteomalacia completely healed. It was concluded that lack of response to calcitriol alone suggests that insufficient dietary calcium might cause osteomalacia, despite adequate supplies of vitamin D.|/OTHER TOXICITY INFORMATION/ 1-alpha-hydroxycholecalciferol ... is synthetic derivative of vitamin D3 that is hydroxylated in 1-alpha position. It is readily hydroxylated in the 25 position by hepatic microsomal system to form 1,25-dihydroxycholecalciferol and was therefore introduced as substitute for this compound. ... Although in theory it should be equivalent to calcitriol, unlike the natural metabolite it has been found at certain dosages to cause progressive increases in absorption of calcium, leading to hypercalcemia that sometimes persist for weeks after therapy is discontinued.

Parenteral: Injection, for IV use only: 1 ug/mL Calcijex, (Abbott); 2 ug/mL Calcijex, (Abbott).|Oral: Capsules: 0.25 ug Rocaltrol (with parabens), (Roche); 0.5 ug Rocaltrol (with parabens), (Roche). Solution: 1 ug/mL Calcitriol Oral Solution, (Roxane), Rocatrol, (Roche).

1-alpha-hydroxycholecalciferol, 1-OHD3, is synthetic derivative of vitamin D3 that is hydroxylated in 1-alpha position. It is readily hydroxylated in the 25 position by hepatic microsomal system to form 1,25-dihydroxycholecalciferol and was therefore introduced as substitute for this compound.

1,25-DIHYDROXYCHOLECALCIFEROL IN BLOOD SERUM WAS DETECTED BY RADIOIMMUNOASSAY.