Molecule

Drug Groups

approved; nutraceutical

Description

Calcitriol or 1,25-dihydroxycholecalciferol (abbreviated 1,25-(OH)₂-D3) is the active form of vitamin D found in the body (vitamin D3). Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott) and Decostriol (Mibe, Jesalis). It is produced in the kidneys via 25-hydroxyvitamin D-1 α-hydroxylase by conversion from 25-hydroxycholecalciferol (calcidiol). This is stimulated by a decrease in serum calcium, phosphate (PO₄^3?) and parathyroid hormone (PTH) levels. It regulates calcium levels by increasing the absorption of calcium and phosphate from the gastrointestinal tract, increasing calcium and phosphate reabsorption in the kidneys and inhibiting the release of PTH. Calcitriol is also commonly used as a medication in the treatment of hypocalcemia and osteoporosis.

Indication

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.

Pharmacology

Calcitriol, a pharmaceutical form of vitamin D, has anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Calcitriol has been found to be effective in the treatment of psoriasis when applied topically. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation in a number of malignant cell lines including human prostate cancer cells. 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. It 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. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.

Toxicity

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

Affected Organisms

Biotransformation

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. The lactone appears to be the major metabolite circulating in humans.

Absorption

Rapidly absorbed from the intestine.

Half Life

5-8 hours

Protein Binding

99.9%

Elimination

Enterohepatic recycling and biliary excretion of calcitriol occur. 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.

Clearance

* 15.3 mL/hr/kg [pediatric patients (age range: 1.8 to 16 years) undergoing peritoneal dialysis receiving dose of 10.2 ng/kg (SD 5.5 ng/kg) for 2 months]

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