Adrovance, Animi-3 With Vitamin D, Citranatal B-calm Kit, Citranatal Harmony, Fosamax Plus D, Fosavance, Infuvite, Infuvite Pediatric, Mvc-fluoride, Natafort, Pregvit, Vidextra, Vantavo (previously Alendronate sodium and colecalciferol, MSD)
Small Molecule
C27H44O
67-97-0
Bone Fractures, Calcium and Vitamin D Deficiencies, Deficiency of Vitamin D3, Deficiency, Vitamin A, Deficiency, Vitamin D, Hip Fracture, Hypoparathyroidism, Hypophosphatemia, Familial, Menopause, Osteomalacia, Osteoporosis, Postmenopausal Osteoporosis, Vertebral Fractures, Vitamin D Resistant Rickets, Vitamin Deficiency, Severe Bone Resorption, Spine fracture
Cholecalciferol, commonly known as Vitamin D3, is a fat-soluble secosteroid that functions as a critical prohormone within the human body. While historically classified as a vitamin, its endogenous synthesis in the skin upon exposure to sunlight and its subsequent multi-organ activation into a potent hormone underscore its central role in a complex endocrine system. The primary and undisputed function of the Vitamin D system is the maintenance of calcium and phosphate homeostasis, which is essential for normal bone mineralization. Consequently, Cholecalciferol is a cornerstone therapy for the prevention and treatment of a range of skeletal disorders arising from its deficiency, including rickets in children, osteomalacia in adults, and as an adjunct with calcium for osteoporosis management.
A significant body of scientific evidence has established the clinical superiority of Cholecalciferol (D3) over its plant-derived counterpart, Ergocalciferol (D2). Studies consistently demonstrate that D3 is more potent and has a longer duration of action in raising and sustaining serum concentrations of 25-hydroxyvitamin D, the key indicator of vitamin D status. This has led to a broad consensus that Cholecalciferol should be the preferred form for both supplementation and therapeutic repletion.
Beyond its classical skeletal functions, the discovery of Vitamin D Receptors (VDR) in nearly all tissues has spurred extensive research into its non-skeletal roles, including immune modulation, cardiovascular health, and cancer prevention. While observational studies frequently report strong correlations between low vitamin D levels and an increased risk of these conditions, large-scale randomized controlled trials have largely failed to demonstrate a causal benefit of supplementation. This disconnect suggests that low vitamin D status may often be a marker or consequence of chronic disease rather than a primary cause.
Clinically, the use of Cholecalciferol requires careful consideration of dosing, which must be tailored to the individual's age, baseline levels, and clinical context. Monitoring of serum 25-hydroxyvitamin D and calcium is essential, particularly with high-dose regimens, to ensure efficacy and prevent toxicity. Hypervitaminosis D, a condition driven by hypercalcemia from excessive supplementation, is a rare but serious risk that underscores the importance of medical supervision. This report provides an exhaustive analysis of Cholecalciferol, covering its fundamental chemistry, physiological pathways, clinical applications, safety profile, and its definitive advantages over Ergocalciferol, serving as a comprehensive reference for healthcare professionals and researchers.
A thorough understanding of Cholecalciferol begins with its precise chemical identity and physical characteristics, which dictate its biological behavior, formulation, and stability.
Cholecalciferol is known by several names across scientific, clinical, and commercial domains. Its systematic name, defined by the International Union of Pure and Applied Chemistry (IUPAC), is (3S,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol. The most common names are Vitamin D3 and its international nonproprietary name (INN), Colecalciferol. It is also referred to by synonyms such as Calciol, Activated 7-dehydrocholesterol, and Oleovitamin D3, reflecting its chemical origin and properties. To facilitate unambiguous identification and data retrieval across global databases, it is assigned a series of unique identifiers.
The structure of Cholecalciferol is fundamentally distinct from classical steroid hormones. It is classified as a seco-steroid, a term derived from the Latin "seco" meaning "to cut". This name reflects its unique origin: it is formed when the B-ring of its precursor molecule, 7-dehydrocholesterol, is cleaved between carbons 9 and 10. This bond cleavage is a photochemical reaction driven by UVB radiation, a process that cannot occur with classical four-ring steroids. This specific structural feature is not merely a chemical curiosity; it is the molecular basis for its identity as the "sunshine vitamin," directly linking its chemical structure to its primary physiological source and its unique role in human biology.
Table 1: Key Identifiers and Physicochemical Properties of Cholecalciferol
Property | Value | Source(s) |
---|---|---|
Primary Names | Cholecalciferol, Vitamin D3, Colecalciferol | |
IUPAC Name | (3S,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol | |
DrugBank ID | DB00169 | |
CAS Number | 67-97-0 | |
PubChem CID | 5280795 | |
ATC Code | A11CC05 | |
Molecular Formula | C27H44O | |
Molar Mass | 384.64 g·mol⁻¹ | |
Physical State | Crystalline solid | |
Solubility | Soluble in ethanol (30 mg/ml), DMSO (2 mg/ml), DMF (25 mg/ml) | |
UNII | 1C6V77QF41 |
Cholecalciferol is a small molecule with the chemical formula C27H44O and a molar mass of approximately 384.64 g·mol⁻¹. As a fat-soluble compound, it is hydrophobic, exhibiting poor solubility in water but good solubility in organic solvents and lipids. This lipophilicity is a critical determinant of its pharmacokinetic profile, influencing its absorption from the gut, its transport in circulation, and its storage in adipose tissue.
In its pure form, Cholecalciferol is a crystalline solid that is sensitive to environmental factors. It is particularly susceptible to degradation by light, oxidation, and the presence of certain minerals. This instability presents challenges for the manufacturing and storage of both pharmaceutical preparations and fortified foods. To overcome this, industrial formulations often employ stabilization techniques. Esterification of the hydroxyl group can enhance stability, as can microencapsulation technologies that coat the molecule with protective matrices like gelatin, sugar, or starch. These strategies protect the active compound from degradation, ensuring potency and shelf-life. For optimal preservation, Cholecalciferol products should be stored at room temperature in tightly sealed, opaque containers, shielded from excess heat and moisture. Under such conditions, the compound is reported to be stable for at least four years.
The human body acquires Cholecalciferol through two distinct pathways: endogenous synthesis in the skin, which is the primary source for most people, and exogenous intake from dietary sources, including natural foods, fortified products, and supplements.[1]
The synthesis of Vitamin D3 in the skin is a remarkable photochemical process. When the skin is exposed to sunlight, specifically type B ultraviolet (UVB) radiation with wavelengths between 290 and 310 nm, the energy is absorbed by a precursor molecule, 7-dehydrocholesterol, which is abundant in the epidermal layers.[1] This absorption of photonic energy triggers an electrocyclic reaction that breaks a bond in the B-ring of the cholesterol precursor, converting it first to previtamin D3 and then, through thermal isomerization, into stable Cholecalciferol (Vitamin D3).[1]
The efficiency of this cutaneous synthesis is highly variable and depends on a multitude of factors:
A crucial feature of this endogenous pathway is its elegant self-regulation. Unlike dietary intake, it is impossible to develop Vitamin D toxicity from sun exposure. Once the body has produced sufficient Vitamin D3, continued UVB exposure begins to degrade the previtamin D3 and Vitamin D3 into inactive photoproducts, preventing excessive accumulation.
While sunlight is the principal source, Cholecalciferol can also be obtained from the diet, although few foods are naturally rich in it.
The confluence of modern societal trends—including predominantly indoor occupations and leisure activities, coupled with robust public health messaging that encourages sun protection to mitigate skin cancer risk—has systematically reduced the opportunity for endogenous Vitamin D synthesis. This reality, combined with the scarcity of natural dietary sources, means that for a large portion of the global population, food fortification and supplementation have transitioned from being merely "supplementary" to being the primary, essential sources for maintaining vitamin D sufficiency. This shift elevates the importance of public health policies on fortification and sound clinical guidance on supplementation from a secondary concern to a cornerstone of preventative medicine.
Table 2: Dietary Sources and Fortification Levels of Vitamin D
Food Source | Serving Size | Vitamin D Content (mcg) | Vitamin D Content (IU) | Source(s) |
---|---|---|---|---|
Cod liver oil | 1 tablespoon | 34.0 | 1,360 | 1 |
Trout (rainbow), farmed, cooked | 3 ounces | 16.2 | 645 | 1 |
Salmon (sockeye), cooked | 3 ounces | 14.2 | 570 | 1 |
Mushrooms, white, UV-exposed | ½ cup | 9.2 (as D2) | 366 (as D2) | 1 |
Milk, 2% milkfat, fortified | 1 cup | 2.9 | 120 | 1 |
Soy, almond, or oat milk, fortified | 1 cup | 2.5–3.6 | 100–144 | 1 |
Ready-to-eat cereal, fortified | 1 serving | 2.0 | 80 | 1 |
Egg, large, scrambled | 1 large | 1.1 | 44 | 1 |
Liver, beef, braised | 3 ounces | 1.0 | 42 | 1 |
Tuna fish (light), canned in water | 3 ounces | 1.0 | 40 | 1 |
Note: 1 mcg of Vitamin D is equivalent to 40 International Units (IU).
The pharmacology of Cholecalciferol is defined by its transformation from an inert prohormone into a potent steroid hormone that regulates the expression of hundreds of genes. This process involves a complex endocrine system with multi-organ activation, tight feedback regulation, and a nuclear receptor-mediated mechanism of action.
The common perception of Vitamin D as a simple vitamin is a historical misnomer that belies its true biological identity. It is more accurately described as a prohormone, the inactive precursor at the head of a sophisticated endocrine pathway. This distinction is not merely semantic; it is fundamental to understanding its physiology, its pleiotropic effects, and its role in disease. Unlike a typical vitamin that acts as a simple enzymatic cofactor, Cholecalciferol initiates a hormonal cascade analogous to that of other steroid hormones like cortisol or estrogen. This perspective explains why its function is so complex, why its activation is tightly regulated by other hormones, and why its effects are so widespread throughout the body.
By itself, Cholecalciferol is biologically inert. To become active, it must undergo a sequential two-step hydroxylation process:
The production of Calcitriol is meticulously controlled by a classic endocrine feedback loop involving several hormones:
Active Calcitriol exerts its biological effects by functioning as a nuclear transcription factor. The process involves several key steps:
The effects of Calcitriol are broadly categorized into classical (skeletal) and non-classical (extra-skeletal) roles.
The pharmacokinetic profile of Cholecalciferol and its metabolites is characterized by its fat-solubility and the long half-life of its major circulating form.
The pharmacokinetic profile of the Vitamin D system, particularly the long half-life of Calcifediol and its substantial storage in adipose tissue, creates what can be described as a "high inertia" system. This means the body's overall vitamin D status does not change rapidly in response to short-term fluctuations in sun exposure or dietary intake. This inertia has two key clinical implications. First, it explains why vitamin D deficiency develops slowly, over a prolonged period of insufficient intake and synthesis, as the body's stores are gradually depleted. Second, it provides the rationale for flexible dosing strategies to correct deficiency. The system's slow dynamics allow for high-dose "loading" regimens—such as large weekly or even monthly doses—to be effective in rapidly replenishing stores, followed by lower daily maintenance doses to sustain adequate levels.
Table 3: Summary of Pharmacokinetic Parameters for Cholecalciferol and its Metabolites
Metabolite Name (Form) | Primary Site of Synthesis | Transport Protein | Metabolic Half-Life | Primary Role | Source(s) |
---|---|---|---|---|---|
Cholecalciferol (Prohormone) | Skin, Diet | GC | ~24 hours | Inactive precursor | 3 |
Calcifediol (25(OH)D) | Liver | GC | ~15 days | Major circulating form; indicator of D status | 3 |
Calcitriol (1,25(OH)2D) | Kidney | GC | ~15 hours | Biologically active hormone | 3 |
The clinical use of Cholecalciferol is centered on its fundamental role in bone and mineral metabolism. While its applications have been explored across a wide range of conditions, a clear distinction exists between its well-established, evidence-based indications and its more speculative, investigational uses.
Cholecalciferol is indicated for the prevention and treatment of conditions directly caused by vitamin D deficiency or dysregulated calcium and phosphate metabolism.
The widespread expression of the VDR has fueled immense interest in the potential non-skeletal benefits of Vitamin D. However, a persistent and telling disconnect exists between promising observational data and the results of definitive randomized controlled trials (RCTs).
Epidemiological studies have consistently reported strong inverse correlations between serum 25(OH)D levels and the risk of numerous chronic diseases, including various cancers, cardiovascular disease, type 2 diabetes, autoimmune disorders, and depression. This led to the plausible hypothesis that correcting low vitamin D levels through supplementation could prevent these conditions. However, when this hypothesis has been tested in large, well-designed RCTs, the results have been overwhelmingly disappointing.
This consistent failure of intervention to replicate observational findings points toward a critical concept in epidemiology: the "correlation versus causation" fallacy and the high likelihood of reverse causality. It is increasingly understood that low vitamin D status is often a consequence or a biomarker of poor health, rather than its cause. For instance, chronic inflammatory conditions can themselves suppress serum 25(OH)D levels. Furthermore, individuals with chronic diseases are often less mobile, spend less time outdoors in the sun, and may have poorer nutritional habits—all independent factors that lead to lower vitamin D levels. Therefore, low vitamin D may simply be an indicator of an underlying unhealthy state (e.g., inflammation, sedentary lifestyle) rather than an independent, modifiable risk factor for these non-skeletal diseases. This understanding is crucial for clinicians to manage patient expectations and to avoid recommending supplementation for unproven benefits.
The effective and safe use of Cholecalciferol requires adherence to appropriate dosing regimens, proper administration techniques, and, when necessary, therapeutic monitoring.
Cholecalciferol is available in a wide variety of oral dosage forms to suit different patient needs, including standard capsules and tablets, chewable tablets, orally disintegrating tablets, liquid-filled gel capsules, and liquid drops for pediatric or sublingual use. As a fat-soluble vitamin, its absorption from the gastrointestinal tract is enhanced when taken with a meal that contains fat. While co-administration with food is recommended for optimal absorption, it can be taken without food.
Dosing of Cholecalciferol is expressed in either International Units (IU) or micrograms (mcg), with the conversion being 1 mcg=40 IU. Recommendations vary based on age, clinical indication, and the guidelines of different health organizations.
It is important to recognize the significant lack of universal consensus among global health organizations regarding the precise definition of optimal serum levels and the corresponding daily intake requirements. Recommendations can vary between countries and medical societies, reflecting different interpretations of the scientific literature and considerations of population-specific factors like diet and typical sun exposure. This variability underscores that clinicians must exercise judgment, tailoring their recommendations to the individual patient's specific risk profile, lifestyle, and clinical goals, rather than relying on a single, one-size-fits-all number.
For individuals on standard, low-dose maintenance supplementation (e.g., 400–1000 IU/day), routine blood testing is generally not necessary. However, monitoring is crucial in several clinical scenarios:
Cholecalciferol has a very wide therapeutic window, and when used at recommended doses, it is exceptionally safe. However, excessive intake can lead to a rare but serious condition known as hypervitaminosis D.
At standard therapeutic and supplemental doses, Cholecalciferol is generally well-tolerated and does not typically cause side effects. When adverse effects do occur, they are usually mild and may include constipation, nausea, or loss of appetite. These symptoms are often early indicators of rising calcium levels and should prompt a re-evaluation of the dosage.
Vitamin D toxicity is a state of pathologically high vitamin D levels in the body. Its clinical manifestations are driven not by vitamin D itself, but by the resulting hypercalcemia.
The wide safety margin of vitamin D is well-established. However, the modern healthcare landscape presents a new challenge. The surge in public interest in vitamin D for a host of unproven benefits, combined with the widespread availability of high-dose OTC supplements, has increased the potential for unsupervised self-medication and iatrogenic toxicity. This situation makes it imperative for clinicians to proactively inquire about all supplement use, educate patients on the principle that "more is not better," and emphasize the risks of exceeding recommended doses without medical guidance.
The use of Cholecalciferol is contraindicated in individuals with:
Caution should be exercised in patients with conditions that can increase sensitivity to vitamin D's effects, such as sarcoidosis, tuberculosis, and some lymphomas, where granulomatous tissue can ectopically produce active Calcitriol, increasing the risk of hypercalcemia.
The widespread use of Cholecalciferol as a supplement necessitates a clear understanding of its potential interactions with other medications. These interactions can be categorized by their underlying mechanism: those that alter calcium homeostasis, those that affect vitamin D metabolism, and those that impair its absorption.
Table 5: Comprehensive Summary of Clinically Significant Drug Interactions with Cholecalciferol
Interacting Drug/Class | Mechanism of Interaction | Clinical Management/Recommendation | Source(s) |
---|---|---|---|
Pharmacodynamic Interactions (Altering Calcium) | |||
Thiazide Diuretics (e.g., Hydrochlorothiazide) | Decrease renal excretion of calcium. Combined with Vitamin D-enhanced intestinal absorption, this can lead to hypercalcemia. | Use with caution, especially in the elderly or those with renal impairment. Monitor serum calcium levels periodically. | 4 |
Digoxin (Lanoxin) | Hypercalcemia (a potential effect of high-dose Vitamin D) increases the risk of digoxin toxicity and cardiac arrhythmias. | Use with extreme caution. Monitor serum calcium and digoxin levels closely. Avoid high-dose Vitamin D supplementation if possible. | |
Pharmacokinetic Interactions (Altering Metabolism) | |||
CYP3A4 Inducers (e.g., certain Antiepileptics) | Induce the cytochrome P450 enzyme system (specifically CYP3A4), which accelerates the catabolism of Vitamin D metabolites, leading to lower serum 25(OH)D levels. | Patients on chronic therapy with these drugs may require higher doses of Vitamin D. Monitor serum 25(OH)D levels to ensure adequacy. | 4 |
- Phenytoin, Fosphenytoin, Carbamazepine, Phenobarbital | |||
- Rifampin (Antitubercular) | 4 | ||
Corticosteroids (e.g., Prednisone) | May impair calcium absorption and potentially interfere with Vitamin D metabolism. Long-term use is a risk factor for osteoporosis. | Patients on long-term steroid therapy should be assessed for Vitamin D status and supplemented with Vitamin D and calcium as needed to preserve bone health. | 4 |
Statins (e.g., Atorvastatin, Simvastatin) | Complex interaction. Both Vitamin D and some statins are metabolized by CYP3A4, leading to competition. The clinical significance appears low, but interactions are possible. | Generally considered safe to co-administer. Clinicians should be aware of the potential for interaction but routine dose adjustments are not typically required. | 4 |
Interactions Affecting Absorption | |||
Bile Acid Sequestrants (e.g., Cholestyramine) | Bind bile acids in the gut, which can interfere with the absorption of fat-soluble vitamins, including Vitamin D. | Administer Vitamin D supplements at least 4 hours before or 4-6 hours after the bile acid sequestrant to avoid impaired absorption. | 4 |
Orlistat (Alli, Xenical) | A lipase inhibitor that blocks the absorption of dietary fat. This directly and significantly reduces the absorption of fat-soluble vitamins like D. | Administer Vitamin D supplements at least 2 hours before or after the Orlistat dose. Monitor Vitamin D status. | |
Mineral Oil | When used as a laxative, it can interfere with the intestinal absorption of fat-soluble vitamins. | Avoid long-term, regular use of mineral oil in patients requiring Vitamin D supplementation. |
A frequent point of clinical discussion and confusion is the difference between the two major forms of vitamin D: Cholecalciferol (D3) and Ergocalciferol (D2). While historically considered equivalent, a robust body of modern evidence has demonstrated significant differences in their metabolism and efficacy, establishing a clear preference for D3 in clinical practice.
The two forms originate from different biological kingdoms and have distinct chemical structures.
Although both forms are absorbed effectively, their subsequent metabolism and ability to raise and maintain vitamin D status are markedly different.
The cumulative evidence strongly supports a clinical preference for Cholecalciferol. Given its superior potency in raising and maintaining serum 25(OH)D, its longer duration of action, greater storage efficiency, and generally lower cost, Cholecalciferol (D3) should be considered the preferred form for all clinical applications, including food fortification, over-the-counter supplementation, and the treatment of vitamin D deficiency.
Table 6: Head-to-Head Comparison: Cholecalciferol (D3) vs. Ergocalciferol (D2)
Feature | Cholecalciferol (Vitamin D3) | Ergocalciferol (Vitamin D2) | Source(s) |
---|---|---|---|
Primary Source | Animal-based (synthesized in skin, fatty fish, egg yolks) | Plant/Fungi-based (mushrooms, yeast, fortified foods) | |
Structural Difference | Standard seco-steroid side chain | Extra methyl group and double bond in the side chain | |
Relative Potency | Significantly more potent in raising serum 25(OH)D | Markedly less potent; estimated at <1/3 to ~1/2 of D3's potency | 5 |
Duration of Action | More sustained effect; longer half-life of resulting 25(OH)D | Shorter duration of action; levels decline more rapidly | 5 |
Body Storage | 2- to 3-fold greater storage in adipose tissue | Less efficient storage | |
Clinical Preference | Preferred form for supplementation and treatment | Less effective alternative; may be used for vegan patients |
Cholecalciferol (Vitamin D3) is far more than a simple vitamin; it is an essential prohormone at the center of a vital endocrine system. Its role in maintaining calcium and phosphate homeostasis and ensuring skeletal health is unequivocally established. The conversion of the inert Cholecalciferol molecule through a tightly regulated, two-step hydroxylation process in the liver and kidneys into the active hormone Calcitriol, which then modulates gene transcription via the Vitamin D Receptor, represents a cornerstone of human mineral metabolism.
The evidence is definitive regarding the clinical superiority of Cholecalciferol (D3) over Ergocalciferol (D2). Its greater potency, longer duration of action, and more efficient storage make it the clear and logical choice for all forms of supplementation and therapeutic repletion. While the discovery of VDRs in nearly every cell type has sparked decades of research into non-skeletal benefits, clinicians and patients must be cautious. The consistent failure of large-scale randomized trials to confirm the promising links seen in observational studies suggests that low vitamin D is more often a marker of ill health than a direct cause of non-skeletal disease. The primary, evidence-based indication for Cholecalciferol supplementation remains the prevention and treatment of bone-related disorders.
Based on this comprehensive analysis, the following recommendations are provided for optimal clinical practice:
Published at: July 14, 2025
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