Generic Name

Vitamin D3 (cholecalciferol)

Mechanism

Vitamin D3 (cholecalciferol) is a fat‑soluble secosteroid that undergoes hepatic 25‑hydroxylation to form 25‑hydroxyvitamin D3 (calcidiol), followed by renal 1α‑hydroxylation to the active form 1,25‑dihydroxyvitamin D3 (calcitriol).
• Receptor Interaction: Calcitriol binds to the vitamin D receptor (VDR), a nuclear transcription factor, inducing expression of genes that regulate calcium and phosphate transport.
• Bone Effects: Enhances intestinal absorption of Ca²⁺ and PO₄³⁻, promotes mineralization, and modulates osteoclast/osteoblast balance.
• Extra‑osseous Actions: Influences immune modulation, cell proliferation, and the synthesis of antimicrobial peptides.

Pharmacokinetics

• Absorption: Oral cholecalciferol requires bile salts; bioavailability ≈ 30–70 % (high‑fat meals increase absorption).
• Distribution: Primarily stored in adipose tissue; plasma protein binding ~ 90‑95 % to vitamin‑D‑binding protein (DBP).
• Metabolism:
• *Liver*: 25‑hydroxylation (CYP2R1) → calcidiol.
• *Kidney*: 1α‑hydroxylation (CYP27B1) → calcitriol; ↓ in chronic kidney disease.
• Half‑life:
• Calcidiol: ~ 15–25 days.
• Calcitriol: ~ 59 hours (short).
• Excretion: Metabolites excreted via bile and feces; renal clearance of Ca²⁺/PO₄³⁻ byproducts.

Indications

Contraindications

• Hypercalcemia or hyperparathyroidism (unless controlled).
• Sclerostin‑knockout or conditions with excessive bone turnover.
• Hepatotoxicity: Avoid in severe liver disease due to accumulation of intermediates.
• Hypervitaminosis D: Monitor serum levels; high doses (> 10 000 IU/day) may lead to toxicity.

Warnings
• Kidney dysfunction: Monitor renal function; higher doses may precipitate nephrolithiasis.
• Pseudohypercalcemia: Elevated 25‑OH D may be due to increased vitamin‑D‑binding protein; interpret cautiously.

Dosing

*Note*: Retail 25‑OH‑D levels should be checked at ~6–12 weeks post‑initiation.

Adverse Effects

• Common
• Nausea, dizziness, fatigue (especially high cumulative doses).
• Mild hypercalcemia → constipation, muscle weakness.
• Serious
• Hypercalcemia (elevated serum Ca²⁺ > 10.2 mg/dL).
• Nephrolithiasis (due to increased urinary Ca²⁺).
• Hypervitaminosis D: Osteomalacia, pancytopenia, cardiac arrhythmias.
• Allergic reaction: Rare cutaneous or anaphylactic reaction.
• Renal dysfunction: Potential for nephrocalcinosis.

Monitoring

• Serum 25‑OH D (ng/mL or nmol/L) every 3–6 months until target achieved.
• Serum calcium and phosphate at baseline, then every 1–3 months for high‑dose therapy.
• Renal function (creatinine, eGFR) for patients on > 50 000 IU/week.
• Urine calcium/creatinine ratio in patients at risk for stones.
• Bone density (DXA) yearly for osteoporosis patients.

Clinical Pearls

• Sun vs. Supplement: Endogenous synthesis provides ~ 10–100 IU/day; chronic sun‑exposure without protection may still result in deficiency due to lifestyle and skin pigmentation.
• Vitamin D3 vs. D2: D3 has a ~ 2‑fold higher conversion to the active form and a longer half‑life; prescriber should prefer D3 over D2 for long‑term therapy.
• Adipose Storage Matters: Patients with obesity may require higher doses due to sequestering in fat tissue.
• CKD Dilemma: In stage 3–4 CKD, cholecalciferol can still raise 25‑OH D, but conversion to calcitriol is limited; active analogues (calcitriol, paricalcitol) may be needed.
• Pregnancy & Lactation: 600 IU daily is generally safe; higher doses are acceptable if deficiency is documented.
• Drug Interactions: Rifampin, anticonvulsants (phenytoin, phenobarbital), glucocorticoids, and cholesterol‑lowering agents (statins) reduce serum vitamin D levels via enhanced metabolism.
• Monitoring Frequency: In patients on high‑dose therapy (≥20 000 IU/day), re‑check serum calcium and 25‑OH D every 2–4 weeks to prevent toxicity.

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• Use this card as a quick reference for pharmacists, clinicians, and medical students to navigate vitamin D3 therapy, dosage tailoring, and patient safety precautions.