Calcitrol

Colorless, crystalline solid

White crystalline powder

Insoluble

Slightly sol in methanol, ethanol, ethyl acetate, THF.

Breast Feeding; Lactation; Milk, Human; Bone Density Conservation Agents; Vitamins; Vitamin D

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Dermatological medicines > Medicines affecting skin differentiation and proliferation

113-114

111-115 °C

113 °C

White solid; [Merck Index]

Solid

Danger

H300 (100%): Fatal if swallowed [Danger Acute toxicity, oral]

P203, P260, P262, P264, P270, P271, P280, P284, P301+P316, P302+P352, P304+P340, P316, P318, P320, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 91 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Calcitriol capsules should be protected from moisture, heat, and light and stored in tight, light-resistant containers at 15-30 °C. Calcitriol oral solution should be protected from light and stored at 15-30 °C. Calcitriol injection should be stored at room temperature (25 °C); freezing should be avoided. Although brief exposure to temperatures up to 40 °C does not adversely affect the injection, exposure to excessive heat should be avoided.

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.

The treatment of acute accidental overdosage of Calcitriol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. 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 a low-calcium diet are also indicated in accidental overdosage. (L1712)

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.

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).

Hypercalcemia is the most common adverse reaction reported in at least one-third of patients taking systemic calcitriol. Early signs of hypercalcemia include fatigue, weakness, nausea, vomiting, abdominal pain, constipation, diarrhea, vertigo, tinnitus, ataxia, arthralgia, and irritability. Late signs of hypercalcemia include polyuria, polydipsia, cardiac arrhythmias, sensory disturbances, apathy, nephrocalcinosis, urinary tract infections, and hypertension.

Signs and Symptoms of Overdose

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.

Overdose evident in elevated blood calcium levels causing symptoms of anorexia, nausea and vomiting, polyuria, polydipsia, weakness, pruritus, and nervousness, potentially with irreversible calcification of soft tissue in the kidney and liver.

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.

/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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Calcitriol

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

A11CC04

D - Dermatologicals

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

QD - Dermatologicals

A11CC04

In adults, vitamin D deficiency results in osteomalacia, a disease characterized by generalized accumulation of underminiralized bone matrix. Severe osteomalacia may be associated with extreme bone pain and tenderness. Muscle weakness, particularly of large proximal muscles, is typical. Its basis is not fully understood but may reflect hypophosphatemia and inadequate vitamin D action on muscle. Gross deformity of bone occurs only in advanced stages of the disease. Circulating 25-OHD (25-hydroxycholecalciferol) concentrations below 8 ng/mL are highly predictive of osteomalacia. /Vitamin D/

The exact physiologic function of vitamin D in brain, heart, pancreas, mononuclear cells, activated lymphocytes, and skin remains unknown, and although the vitamin exhibits potent antiproliferative and prodifferentiation effects, there currently is little evidence that vitamin D deficiency results in major disorders in these organs and cellular systems. The possibility that vitamin D deficiency may be associated with an increased risk of colon, breast, and prostate cancer has been suggested by epidemiologic evidence from individuals living in higher latitudes, but current evidence is too limited to indicate categorically a cancer risk associated with deficiency. /Vitamin D/

Vitamin D deficiency causes decreased ionized calcium concentrations in blood and a resultant increase in the production and secretion of PTH. PTH stimulates the mobilization of skeletal calcium, inhibits renal excretion of calcium, and stimulates renal excretion of phosphorus resulting in normal fasting serum calcium concentrations and low or near-normal serum phosphorus. The enhanced mobilization of skeletal calcium induced by this secondary hyperparathyroidism results in porotic bone. /Vitamin D/

Vitamin D deficiency results in inadequate mineralization of bone or compensatory skeletal demineralization. In children, vitamin D deficiency leads to rickets as a result of inadequate mineralization of bone and is characterized by widening of the end of long bones, rachitic rosary, skeletal deformations (e.g., frontal bossing), and outward and inward deformities of the lower limbs resulting in bowed legs and knocked knees, respectively. In adults, vitamin D deficiency leads to a mineralization defect resulting in osteomalacia. /Vitamin D/

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 <i>Mycobacterium tuberculosis</i>. 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.

The mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)₂-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)₂-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells. A study suggests that calcitriol plays an immunoregulatry role by suppressing the aryl hydrocarbon receptor (AhR) expression in human Th9, a pro-inflammatory CD4 T cell subset. This suppression subsequently leads to repressed expression of BATF, a transcription factor essential for Th9. Calcitriol has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes.

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.

After administration of single oral doses, the elimination half life was 5-8 hours.

Plasma half-life: 3 to 6 hours.

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.

FXC9231JVH

CALCITRIOL

Chemical Structure [CS] - Cholecalciferol

Established Pharmacologic Class [EPC] - Vitamin D3 Analog

Calcitriol is a Vitamin D3 Analog.

CALCITRIOL

Agents that increase calcium influx into calcium channels of excitable tissues. This causes vasoconstriction in VASCULAR SMOOTH MUSCLE and/or CARDIAC MUSCLE cells as well as stimulation of insulin release from pancreatic islets. Therefore, tissue-selective calcium agonists have the potential to combat cardiac failure and endocrinological disorders. They have been used primarily in experimental studies in cell and tissue culture.

Hormones and molecules with calcium-regulating hormone-like actions that modulate OSTEOLYSIS and other extra-skeletal activities to maintain calcium homeostasis.

Organic substances that are required in small amounts for maintenance and growth, but which cannot be manufactured by the human body.

Agents that inhibit BONE RESORPTION and/or favor BONE MINERALIZATION and BONE REGENERATION. They are used to heal BONE FRACTURES and to treat METABOLIC BONE DISEASES such as OSTEOPOROSIS.

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.

Active form of vitamin D3 used therapeutically (calcium regulator, vitamin, antihyperparathyroid, antineoplastic, and antipsoriatic); [Merck Index]

MEDICATION

Bone Density Conservation Agents; Calcium Channel Agonist; Vitamins

Regulates turnover of calcium in the body.

Consumption (g per capita) in the USA (2002): 2.16e-08

Used to treat vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis. Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.

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.