1-alpha-25-Dihydroxyvitamin D3

1-alpha-25-Dihydroxyvitamin D3 Uses, Dosage, Side Effects, Food Interaction and all others data.

1-alpha-25-Dihydroxyvitamin D3 is one of the most important active metabolites of vitamin D3. It is normally formed in the kidney from its precursor, 25-hydroxycolecalciferol (25-HCC). Physiological daily production is normally 0.5-1.0 mcg and is somewhat higher during periods of increased bone synthesis (e.g. growth or pregnancy). 1-alpha-25-Dihydroxyvitamin D3 promotes intestinal absorption of Calcium and regulates bone mineralization.

1-alpha-25-Dihydroxyvitamin D3 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 . 1-alpha-25-Dihydroxyvitamin D3 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 . 1-alpha-25-Dihydroxyvitamin D3 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.

1-alpha-25-Dihydroxyvitamin D3
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	1-alpha-25-Dihydroxyvitamin D3
Availability	Prescription only
Generic	Calcitriol
Calcitriol Other Names	1-alpha-25-Dihydroxyvitamin D3, Calcitriol, Calcitriolum
Related Drugs	ergocalciferol, calcium carbonate, Caltrate, Drisdol, calcium lactate, Rocaltrol, calcifediol, Calcidol
Type
Formula	C₂₇H₄₄O₃
Weight	Average: 416.6365 Monoisotopic: 416.329045274
Protein binding	Calcitriol is approximately 99.9% bound in blood, mostly by an alpha-globulin vitamin D binding protein .
Groups	Approved, Nutraceutical
Therapeutic Class	Vitamin in bone formation, Vitamin-D preparations
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

1-alpha-25-Dihydroxyvitamin D3 is used for the correction of the abnormalities of Calcium and Phosphate metabolism in patients with renal osteodystrophy.

1-alpha-25-Dihydroxyvitamin D3 is also used for the treatment of established post-menopausal osteoporosis, hypoparathyroidism, idiopathic hypoparathyroidism, pseudohypoparathyroidism, vitamin D dependent rickets.

1-alpha-25-Dihydroxyvitamin D3 is also used to associated treatment for these conditions: Hypocalcemia, Osteodystrophy, Psoriasis Vulgaris (Plaque Psoriasis), Secondary Hyperparathyroidism (SHPT), Vitamin D Resistant Rickets

How 1-alpha-25-Dihydroxyvitamin D3 works

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 1-alpha-25-Dihydroxyvitamin D3 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 1-alpha-25-Dihydroxyvitamin D3 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 . 1-alpha-25-Dihydroxyvitamin D3 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.

Dosage

1-alpha-25-Dihydroxyvitamin D3 dosage

Injection

The recommended intravenous initial dose of 1-alpha-25-Dihydroxyvitamin D3 injection, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals.

Capsule

Adult

Renal osteodystrophy: The initial daily dose is 0.25 mcg of 1-alpha-25-Dihydroxyvitamin D3. In patients with normal or only slighty reduced Calcium level, doses of 0.25 mcg every other day are sufficient. If no satisfactory response in the biochemical parameters and clinical manifestations of the disease is observed within 2-4 weeks, the daily dosage may be increased by 0.25 mcg at 2-4 week intervals.

Post-menopausal osteoporosis: The recommended dose of 1-alpha-25-Dihydroxyvitamin D3 is 0.25 mcg twice daily.

Serum calcium and creatinin levels should be determined at 1-3 and 6 months and at 6 monthly intervals thereafter.

Hypoparathyroidism & Rickets: The recommended initial dose of 1-alpha-25-Dihydroxyvitamin D3 is 0.25 mcg per day in the morning. In patients with renal osteodystrophy or hypoparathyroidism and rickets if within 2-4 weeks no satisfactory response is observed by usual dose then dose may be increased at two to four week intervals.

Elderly patients

No specific dosage modifications are required in elderly patents.

Children

Dosage in children has not been established.

Side Effects

Since 1-alpha-25-Dihydroxyvitamin D3 exerts vitamin D activity, adverse effects may occur which are similar to those found when an excessive dose of vitamin D is taken, i.e. hypercalcaemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcaemia). Occasional acute symptoms include anorexia, headache, nausea, vomiting, abdominal pain or stomach ache and constipation.

Toxicity

LD₅₀ (oral, rat) = 620 μg/kg; LD₅₀ (intraperitoneal, rat) > 5 mg/kg .

Symptoms of calcitriol toxicity mirrors the early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia . Early signs include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. Late signs are characterized by polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis .

Precaution

Immobilised patients, e.g. those who have undergone surgery, are particularly exposed to the risk of hypercalcaemia. Patients with normal renal function who are taking 1-alpha-25-Dihydroxyvitamin D3 should avoid dehydration. Adequate fluid intake should be maintained.

Interaction

Concomitant treatment with a thiazide diuretic increases the risk of hypercalcaemia. 1-alpha-25-Dihydroxyvitamin D3 dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcaemia in such patients may precipitate cardiac arrhythmias. Administration of enzyme inducers such as phenytoin or phenobarbital may lead to increased metabolism and hence reduced serum concentrations of 1-alpha-25-Dihydroxyvitamin D3. Therefore higher doses of 1-alpha-25-Dihydroxyvitamin D3 may be necessary if these drugs are administered simultaneously. Colestyramine can reduce intestinal absorption of fat-soluble vitamins and therefore may impair intestinal absorption of 1-alpha-25-Dihydroxyvitamin D3.

Food Interaction

No interactions found.

1-alpha-25-Dihydroxyvitamin D3 Drug Interaction

Major: ergocalciferol, ergocalciferol, cholecalciferol, cholecalciferolUnknown: aspirin, aspirin, furosemide, furosemide, metoprolol, metoprolol, metoprolol, metoprolol, levothyroxine, levothyroxine, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid

1-alpha-25-Dihydroxyvitamin D3 Disease Interaction

Major: arrhythmia, electrolyte imbalance, hypercalcemia, renal dysfunctionModerate: dialysis, hepatobiliary dysfunction

Volume of Distribution

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 . 1-alpha-25-Dihydroxyvitamin D3 from maternal circulation may also enter the fetal circulation .

Elimination Route

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 .

Half Life

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

Clearance

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 .

Elimination Route

In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours . 1-alpha-25-Dihydroxyvitamin D3 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 .

Pregnancy & Breastfeeding use

Pregnancy category C. 1-alpha-25-Dihydroxyvitamin D3 has been found to be teratogenic in rabbits. There are no adequate and well-controlled studies in pregnant women. 1-alpha-25-Dihydroxyvitamin D3 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Contraindication

1-alpha-25-Dihydroxyvitamin D3 is contraindicated in patients with known hypersensitivity to any of its ingredients. 1-alpha-25-Dihydroxyvitamin D3 is also contraindicated in all diseases associated with hypercalcemia.

Special Warning

Elderly patients: No specific dosage modifications are required in elderly patients.

Acute Overdose

Administration of 1-alpha-25-Dihydroxyvitamin D3 to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphospatemia. Since 1-alpha-25-Dihydroxyvitamin D3 is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D.