Vitamin D

Introduction Overview

Generic Name

Vitamin D

Brand Name

D3, Delta D3, D3-5, D3-50, Bio-D-Mulsion Forte

Dosage Form

Oral tablet, chewable tablet, oral liquid, capsule, and injectable forms (varies by preparation)

Drug Class

Vitamins; Prohormones

Pharmacokinetics

Vitamin D pharmacokinetics involves complex absorption, distribution, metabolism, and elimination pathways owing to its lipophilic nature and prohormone status.

Absorption: Vitamin D, being fat-soluble, is absorbed in the small intestine with the aid of bile salts in micellar form and incorporated into chylomicrons for lymphatic transport. Absorption efficiency can be influenced by dietary fat content, gastrointestinal integrity, and the presence of malabsorption syndromes such as celiac disease, pancreatic insufficiency, or liver disease. Oral vitamin D3 is generally better absorbed than vitamin D2 due to its molecular structure and biological affinity.

Distribution: After absorption, vitamin D is transported via chylomicrons into the lymphatic system and subsequently enters systemic circulation. It binds to vitamin D-binding protein (DBP) to a large extent (~85-90%), facilitating transport to target tissues. Because of its fat solubility, vitamin D is stored in adipose tissue and muscle, serving as a reservoir that modulates plasma levels and bioavailability. Obese individuals often have lower circulating vitamin D levels due to sequestration in fat stores.

Metabolism: Vitamin D undergoes two critical hydroxylation steps. First, in the liver, vitamin D (either D2 or D3) is hydroxylated by 25-hydroxylase enzymes (CYP2R1 and CYP27A1) to form 25-hydroxyvitamin D (25(OH)D, calcidiol), the major circulating and stable metabolite used to assess vitamin D status. Next, in the kidney, 25(OH)D is hydroxylated by 1 alpha-hydroxylase (CYP27B1) to produce the biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol). This step is tightly regulated by parathyroid hormone, calcium, phosphate levels, and fibroblast growth factor 23 (FGF23). Several medications (e.g., anticonvulsants, rifampin) can induce hepatic enzymes, increasing metabolism and reducing vitamin D levels.

Elimination: Vitamin D metabolites are catabolized predominantly via CYP24A1-mediated 24-hydroxylation, leading to water-soluble inactive metabolites excreted in bile and urine. The half-life of 25(OH)D is approximately 15 days, much longer than the active 1,25(OH)2D, which has a half-life of 4–6 hours. Because vitamin D and its metabolites are fat-soluble, elimination is slow and storage in fat can prolong systemic exposure.

Dosage Forms

Available Dosage Forms: Vitamin D is available in several pharmaceutical forms including:
- Oral capsules and softgels containing vitamin D3, commonly ranging from 400 IU, 600 IU, 1000 IU, up to high doses of 50,000 IU for therapeutic use.
- Oral chewable tablets, often formulated with vitamin D3, in doses such as 400 IU, 1000 IU, suitable for pediatric and adult use.
- Oral liquid formulations (drops or suspensions), enabling flexible dosing, often used in infants and those requiring precise dose adjustments. Concentrations vary but typically include 400 IU/mL and other strength variations.
- Injectable preparations (usually prescription-only and limited to specific clinical indications involving parenteral vitamin D analogs).

Dosages for Adults and Adolescents: The recommended daily intake varies by age and clinical condition. Typical dosages include:
- Infants (birth to 1 year): 400 IU/day to prevent deficiency.
- Children and adolescents (1–70 years): 600 IU/day to maintain sufficient levels.
- Adults over 70 years: 800 IU/day recognizing decreased dermal synthesis and absorption efficiency.
- Therapeutic dosages for deficiency or certain disorders can be substantially higher (e.g., 50,000 IU weekly for short durations).
- Safe upper intake limit generally regarded as 4,000 IU/day for healthy adults, with careful monitoring when exceeded.

Specific Patient Populations: Special considerations apply to various populations:
- Infants, especially those exclusively breastfed, require supplementation to prevent deficiency.
- Elderly individuals may require higher supplementation due to reduced skin synthesis and dietary intake.
- Patients with malabsorption (e.g., celiac disease, pancreatic insufficiency) may need monitored, higher oral or parenteral doses.
- Obese patients may necessitate increased dosing due to sequestration in fat stores.
- Patients with chronic kidney or liver disease require tailored dosing due to impaired metabolism.
- Vegetarians or vegans can use vitamin D2 or vegan-sourced D3 supplements (extracted from lichen).

Clinical guidelines recommend monitoring serum 25(OH)D levels to individualize dosing in patients with deficiency or at risk.

Mechanism Of Action

Vitamin D primarily functions as a prohormone, undergoing metabolic activation to exert its biological effects at the molecular and cellular levels. Upon conversion to active 1,25-dihydroxyvitamin D (calcitriol) mainly in the kidneys, the hormone binds with high affinity to the vitamin D receptor (VDR), a nuclear receptor present in numerous tissues including bone, intestines, kidneys, parathyroid glands, and many extraskeletal sites.

The VDR-calcitriol complex heterodimerizes with the retinoid X receptor (RXR) and translocates into the nucleus where it interacts with vitamin D response elements (VDREs) present in promoter regions of vitamin D-regulated genes. This genomic action modulates transcription of genes involved in calcium and phosphate homeostasis, bone mineralization, immune regulation, and cellular proliferation/differentiation.

Clinically, vitamin D’s principal effect is to enhance intestinal absorption of calcium and phosphate by upregulating the expression of calcium-binding proteins (such as calbindin), and phosphate transporters, thus maintaining serum calcium levels and supporting bone mineralization. It also modulates parathyroid hormone (PTH) secretion, providing negative feedback to prevent secondary hyperparathyroidism.

Beyond mineral metabolism, vitamin D influences immune responses by promoting innate immunity and modulating adaptive immunity, affecting T cell differentiation and cytokine production. Research also shows vitamin D's involvement in cell cycle regulation and potential anti-proliferative effects relevant to cancer risk reduction.

Compared to other compounds like ergocalciferol (vitamin D2), cholecalciferol (vitamin D3) exhibits greater potency and more efficient conversion to active metabolites, contributing to more effective activation of VDR-mediated pathways. Clinical trials have demonstrated superior efficacy of D3 over D2 in raising and maintaining serum 25(OH)D concentrations.

Extensive research supports vitamin D’s role in preventing rickets, osteoporosis, and other conditions linked to impaired calcium metabolism. Emerging data also explore its implications for cardiovascular, metabolic, and autoimmune diseases within the framework of its molecular mechanisms.

Pharmacological Actions

Enhances intestinal absorption of calcium and phosphate essential for bone mineralization
Regulates parathyroid hormone secretion through negative feedback mechanisms
Modulates immune system function by promoting innate immunity and regulating T cell responses
Influences cellular proliferation, differentiation, and apoptosis contributing to tissue homeostasis
Acts as a hormone binding to nuclear vitamin D receptors to regulate gene expression
Contributes to maintenance of serum calcium and phosphate concentrations within normal ranges
Reduces risk of rickets and osteomalacia by ensuring adequate mineral availability for bone formation
Participates in cardiovascular system modulation via VDRs located in the heart and vasculature
Supports muscle function and reduces risk of falls in elderly populations
Potential anti-inflammatory effects impacting chronic disease pathogenesis
Regulates calcium transport proteins (eg, calbindin) in the intestines and kidneys
Increases bone remodeling and osteoblast activity to maintain skeletal integrity
Improves skin health through impacts on keratinocyte proliferation and differentiation
Modulates insulin secretion and sensitivity, with implications in diabetes management
Exerts neuroprotective roles influencing cognition and mood via central nervous system VDRs

Therapeutic Or Clinical Uses

Prevention and treatment of vitamin D deficiency and insufficiency
Management of rickets in children and osteomalacia in adults
Prevention of osteoporosis and reduction of fracture risk, especially in elderly
Adjunctive therapy in hypoparathyroidism for calcium homeostasis
Supportive treatment in chronic kidney disease for maintaining mineral metabolism
Use in prevention of falls in at-risk populations, including nursing home residents
Correction of hypocalcemia related to vitamin D deficiency
Potential role in reducing risk and progression of certain cancers (e.g., colon cancer)
Adjunctive treatment in autoimmune diseases and inflammatory conditions
Improvement of muscle strength and function in various neuromuscular disorders
Support in chronic liver disease to counteract malabsorption and metabolic deficits
Therapeutic use in familial hypophosphatemia and related metabolic bone disorders
Use in pregnant and breastfeeding women to ensure adequate maternal and neonatal vitamin D status
Potential preventive role in respiratory infections and severe asthma management
Emerging applications in cardiovascular health and metabolic syndrome interventions

Side Or Adverse Effects

Hypercalcemia leading to nausea, vomiting, constipation, and abdominal pain
Fatigue and weakness associated with excessive vitamin D intake
Polyuria and polydipsia due to hypercalcemia and associated renal effects
Hypercalciuria with risk of nephrolithiasis (kidney stones)
Headaches and dizziness linked to vitamin D intoxication
Soft-tissue and vascular calcification in severe or prolonged overdose
Pruritus and dermatological reactions in hypersensitive individuals
Bone pain and abnormal bone remodeling with toxic levels
Renal impairment or kidney failure secondary to chronic hypercalcemia
Potential interaction-induced decrease in vitamin D efficacy with some medications
Allergic reactions or hypersensitivity to vitamin D formulations (rare)
Gastrointestinal disturbances such as diarrhea or abdominal discomfort
Risk of vitamin K2 depletion with very high vitamin D doses leading to paradoxical bone loss
Muscle pain or cramps at supra-physiological dosing
Electrolyte imbalances such as hypophosphatemia or hypomagnesemia in some contexts

Precautions

Use caution in patients with disorders of calcium metabolism or hypercalcemia
Monitor serum calcium and 25(OH)D levels during high-dose supplementation
Avoid excessive sun exposure combined with supplementation to prevent toxicity
Careful dosing in patients with renal impairment or chronic kidney disease
Consider potential drug interactions with anticonvulsants, rifampin, and glucocorticoids
Adjust dosage in individuals with malabsorption syndromes
Use pregnancy category guidance to balance maternal benefit and fetal risk
Patients with sarcoidosis or granulomatous diseases may have increased sensitivity to vitamin D
Monitor infants and children closely for dosing to avoid toxicity
Advise patients on the risks of self-medicating with high-dose vitamin D supplements
Consider obesity-related sequestration impacting dosing and response
Advise individuals covering skin for religious or cultural reasons on supplementation needs
Caution in patients with history of nephrolithiasis or renal calcinosis
Adjust doses in hepatic dysfunction due to altered hydroxylation
Evaluate vitamin D status as part of metabolic bone disease workup before supplementation

Warnings

Vitamin D toxicity is rare but can lead to life-threatening hypercalcemia
Excessive dosing above the upper safe limit (generally 4,000 IU/day) without medical supervision is not recommended
Routine screening for vitamin D deficiency in asymptomatic individuals remains controversial
Patients with low baseline vitamin D should be supplemented cautiously and monitored
Avoid high-dose supplementation without documented deficiency
Potential for drug interactions reducing efficacy or increasing metabolism
Vitamin D supplements derived from lanolin may not be suitable for vegans or those with allergies
Overuse can result in renal failure due to calcium deposition in kidneys
Not to be used as a substitute for direct sunlight exposure or balanced diet in healthy populations
Inaccurate blood assays may misrepresent vitamin D status leading to inappropriate dosing
Children and infants require carefully adjusted dosing to prevent toxicity
Beware of fortification overlap leading to inadvertent excess intake
Vitamin D should not be used as monotherapy for conditions like osteoporosis without adjunctive therapies
Monitor patients receiving drugs that induce or inhibit vitamin D metabolism
Patients with granulomatous diseases may generate excessive active vitamin D, risking toxicity

Contraindication

Hypercalcemia of any cause
Vitamin D toxicity or hypersensitivity to any vitamin D preparation
Patients with evidence of vitamin D-induced hypercalciuria or hypercalcemia
Severe renal impairment without supervision due to altered metabolism
Sarcoidosis, tuberculosis, or other granulomatous diseases without medical consultation
Primary hyperparathyroidism unless closely monitored
Known hypersensitivity or allergy to ingredients in the vitamin D product
Use caution or contraindicated in patients receiving large doses of digitalis due to risk of arrhythmias
Severe malabsorption not corrected may limit oral vitamin D benefit
Infants with inherited disorders of vitamin D metabolism unless under specialist care
Care with concurrent use of calcium supplements in patients with predisposition to kidney stones
Avoid in patients with hypervitaminosis D
Caution in those with genetic calcium metabolism disorders such as familial hypercalcemia
Contraindicated in unmonitored long-term high-dose therapy
Patients with severe liver disease where biotransformation is impaired unless supervised

Drug Interactions

Anticonvulsants (carbamazepine, phenytoin, phenobarbital, primidone) reduce vitamin D levels by inducing hepatic enzymes
Rifampin induces cytochrome P450 enzymes leading to increased catabolism of vitamin D
Glucocorticoids can impair vitamin D metabolism and calcium absorption
Thiazide diuretics may potentiate hypercalcemia when combined with vitamin D
Ketoconazole inhibits vitamin D activation metabolism and may decrease efficacy
Cholestyramine and orlistat may reduce vitamin D absorption due to fat malabsorption
Calcium supplements may increase risk of hypercalcemia during vitamin D therapy
Statins may interact with vitamin D metabolism through shared cytochrome pathways
Loop diuretics can cause hypocalcemia which may influence vitamin D requirements
Digoxin toxicity risk is increased in the presence of hypercalcemia from vitamin D supplementation
Anti-retroviral drugs like efavirenz may induce metabolism and lower vitamin D levels
Vitamin D supplements may affect serum levels of phosphate and alkaline phosphatase potentially interacting with other metabolic drugs
Possible interaction with magnesium-lowering medications necessitating magnesium monitoring
Concurrent use with vitamin A and vitamin K supplements warrants monitoring for synergistic effects
CYP450 inhibitors or inducers may alter vitamin D conversion, requiring dose adjustments

Preparations Of The Drug

Ergocalciferol (Vitamin D2) - derived from irradiated fungi and plant sources, vegan-friendly
Cholecalciferol (Vitamin D3) - derived from lanolin in sheep's wool or from lichen for vegan formulations
Oral capsules and softgels with varying IU strengths (400 IU to 50,000 IU)
Chewable tablets, often flavored, for pediatric and adult use
Liquid oral drops for infants and adults requiring dose flexibility
Injectable vitamin D analogs for use in specific medical conditions under supervision
Fortified foods including dairy products, breakfast cereals, margarine, infant formulas
Vitamin D analogs with specific modifications for use in kidney disease or hypoparathyroidism
Combination supplements containing calcium and vitamin D for bone health
Over-the-counter vitamin D supplements in various formulations and dosages
Synthetic preparations used in clinical trials and specialized treatments
Vegan-certified vitamin D3 preparations extracted from lichens (e.g., 'Vitashine')
Pharmaceutical grade ergocalciferol tablets (e.g., Drisdol) used for prescription treatment
Bio-D-Mulsion Forte – a vitamin D3 oral emulsion formulation for enhanced absorption
Generic and branded preparations with standard labeling compliant with regulatory authorities