Cholecalciferol
Cholecalciferol
Generic Name
Cholecalciferol
Mechanism
- Active Metabolite Formation
1. Hepatic 25‑hydroxylation → 25‑hydroxycholecalciferol (calcidiol)
2. Renal 1α‑hydroxylation → 1,25‑dihydroxycholecalciferol (calcitriol), the biologically active form
• Receptor Binding
– Binds to intracellular vitamin D receptor (VDR) in target tissues (bone, intestine, immune cells).
• Gene Transcription Modulation
– VDR–calcitriol complex heterodimerizes with retinoid X receptor (RXR).
– Induces transcription of genes encoding calcium‑binding proteins (e.g., *calbindin*), bone matrix proteins, and regulators of bone remodeling.
• Clinical Consequence
– Enhances intestinal calcium and phosphate absorption, promotes bone mineralization, and modulates immune responses.
Pharmacokinetics
| Parameter | Detail |
| Absorption | Oral: ~75 % bioavailability; absorption enhanced by dietary fat. |
| Distribution | Widely distributed in adipose tissue; high plasma protein binding (~90 % to albumin and α1‑acid glycoprotein). |
| Metabolism | Liver → 25‑hydroxycholecalciferol (calcidiol) via CYP2R1; kidney → 1,25‑dihydroxycholecalciferol via CYP27B1. |
| Half‑life | Calcidiol: ~15 days; calcitriol: ~15 hrs. |
| Excretion | Primarily fecal elimination; negligible renal excretion. |
| Factors Influencing PK | Malabsorption (celiac disease), obesity (increased depot), hepatic impairment, drug interactions (rifampin ↑ metabolism, anticonvulsants ↓ levels). |
Indications
- Prevention of vitamin D deficiency in at‑risk populations (infants <1 yr, nursing‑home residents, institutionalized patients).
- Treatment of vitamin D‑deficiency rickets (childhood and juvenile), osteomalacia, and osteoporosis when calcium levels are adequate.
- Adjunctive in calcium‑suppressive therapy (e.g., hyperparathyroidism) and in immune‑mediated diseases (e.g., multiple sclerosis).
- Supplementation in solid‑organ transplant recipients and in chronic kidney disease (CKD) stages 1‑3 (CKD 4‑5: active vitamin D analogues preferred).
Contraindications
- Contraindications
– Hypercalcemia or hyperphosphatemia.
– Hypervitaminosis D (serum 25‑OH‑D > 100 ng/mL).
• Warnings
– Hypercalcemia risk – Monitor serum calcium in patients with renal impairment, sarcoidosis, or lymphoma.
– Kidney disease – CKD ≥ stage 4: avoid high‑dose cholecalciferol; use active analogues.
– Drug interactions – Rifampin, phenobarbital, phenytoin ↑ catabolism; oral contraceptives ↑ hepatic CYP3A4.
– Pregnancy & lactation – Generally safe; ensure adequate intake.
Dosing
| Condition | Typical Dose | Administration | Notes |
| Infants < 1 yr | 400 IU/day | Oral (drops or tablet) | 1 µg/kg/day up to 8 µg/kg. |
| Adults (prevention) | 600–800 IU/day | Oral | 1000 IU may be recommended if low baseline. |
| Rickets / Osteomalacia | 1000–2000 IU/day | Oral | May increase to 50 000 IU weekly for 6–12 weeks in severe deficiency. |
| Maintenance | 800–2000 IU/day | Oral | Adjust per 25‑OH‑D levels. |
| CKD 1–3 | 1000–4000 IU/day | Oral | Monitor calcium and phosphate. |
| High‑Dose Regimen | 50 000 IU weekly | Oral | For rapid repletion; watch for toxicity. |
Route: Oral capsules, tablets, or liquid formulation. Bioavailability ↑ with a fatty meal.
Adverse Effects
- Common (≤ 5 % incidence)
- Abdominal discomfort, nausea, vomiting.
- Mild hypercalcemia symptoms (fatigue, polyuria).
- Serious (≤ 1 %)
- Hypercalcemia → nephrolithiasis, pruritus, cardiovascular arrhythmias.
- Hypervitaminosis D → soft‑tissue calcification, nephrocalcinosis, bone pain.
- Allergic reactions (rare).
Monitoring
| Parameter | Target Range / Frequency | |
| Serum 25‑OH‑D | 20–50 ng/mL (800–2000 IU/day) | Baseline, 4 weeks post‑treatment, then every 3–6 months. |
| Serum Calcium (ionized) | 4.5–5.6 mg/dL | Baseline; every 4 weeks in high‑dose or renal disease. |
| Serum Phosphate | 2.5–4.5 mg/dL | Baseline, monitor with calcium. |
| Renal Function (CrCl) | Baseline; monitor in CKD or high‑dose. | |
| PTH (if present) | Helps gauge response in CKD. | 6–12 months. |
Clinical Pearls
- Fat‑Soluble Advantage – Cholecalciferol's long half‑life means once‑weekly dosing can be reliably used for repletion, but requires vigilant calcium monitoring.
- “Silent” Hypervitaminosis – Because symptoms are nonspecific, routine serum 25‑OH‑D checks are essential in patients on > 4000 IU/day or with malabsorption syndromes.
- Obesity Penalty – Adipose sequestration may lower circulating levels; obese patients often need 25 % higher doses.
- Kidney‑Dependent Activation – In CKD 4–5, the rate‑limiting renal 1α‑hydroxylation step is compromised; use 1,25‑dihydroxyvitamin D analogues instead of cholecalciferol.
- Seasonal Supplementation – Patients living at high latitudes (> 35 ° N) often need > 2000 IU/day during winter months to maintain 25‑OH‑D > 20 ng/mL.
- Dietary Synergy – Pair cholecalciferol with calcium‑rich foods (milk, fortified cereals) for optimal bone health.
*Reference:* European Medicines Agency (EMA), FDA prescribing information, and recent reviews in *Endocrine Reviews* (2024).