Calcitriol

White solid; [Merck Index]

Solid

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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.