Vitamin D3 (Cholecalciferol) and Calcitriol

Mechanism

Activation and biosynthesis pathways

The synthesis and metabolic activation of vitamin D requires a sequence of reactions in three different organs:

SKIN PHOTO-SYNTHESIS 7-Dehydrocholesterol to Pre-D3

Solar ultraviolet B radiation (UVB, 290-315 nm) affects the 7-dehydrocholesterol present in the stratum spinosum of the epidermis, breaking the steroid B ring to form previtamin D₃, which undergoes spontaneous thermal isomerization to cholecalciferol (Vitamin D₃).

LIVER HYDROXYLATION Synthesis of 25-Hydroxyvitamin D [25(OH)D]

Cholecalciferol transported to the liver by vitamin D binding protein (DBP) is hydroxylated at the C25 position by the mitochondrial enzyme CYP2R1 (25-hydroxylase), generating calcifediol, the most abundant reserve form and the best marker of the body status of the vitamin.

KIDNEY ACTIVATION Synthesis of 1,25-Dihydroxyvitamin D [1,25(OH)₂D]

In the renal proximal convoluted tubule, the mitochondrial enzyme CYP27B1 (1α-hydroxylase) adds a second hydroxyl group at the C1 position to form calcitriol, the hormonally active ligand. This enzyme is directly stimulated by parathyroid hormone (PTH) and hypophosphatemia, and inhibited by fibroblast growth factor 23 (FGF-23) and calcitriol itself.

Renal conversion is governed by the following reaction catalyzed by CYP27B1:

Genomic Mechanism of Action in the Enterocyte

Free calcitriol diffuses into the enterocytes and binds to the Vitamin D Receptor (VDR). The calcitriol-VDR complex associates with the RXR receptor and translocates to the nucleus, binding to vitamin D response elements (VDRE). This promotes the transcription of transport proteins involved in active calcium absorption:

• TRPV6: Apical epithelial calcium channel that facilitates the entry of the cation into the enterocyte.
• Calbindin-D9k: Intracellular transporter protein that sequesters free calcium, preventing inappropriate signaling and facilitating its diffusion to the basolateral membrane.
• PMCA1b: Basolateral calcium ATPase pump that expels calcium into the portal circulation.

Pharmacokinetics

Pharmacokinetics

• Absorption: Passive absorption in the small intestine (jejunum and ileum), requiring the presence of bile acids for its emulsification and formation of micelles.
• Distribution: It circulates 85% - 90% bound to DBP and 10% - 15% to albumin. A minimal fraction diffuses freely. It accumulates in body adipose tissue and skeletal muscle.
• Inactivation Metabolism: The enzyme CYP24A1 (24-hydroxylase) hydroxylates both calcifediol and calcitriol at the C24 position, initiating the catabolic cascade toward calcitroic acid, a water-soluble inactive metabolite eliminated by bile.

Security

Contraindications, Adverse Effects and Interactions

Absolutely contraindicated in Active hypercalcemia, vitamin D toxicity or suspected sarcoidosis (granulomatous macrophages autonomously express CYP27B1 not regulated by parathyroid hormone, inducing severe hypercalcemia).

Persistent overdose causes nausea, vomiting, polyuria, polydipsia, dehydration, ectopic soft tissue calcification (nephrocalcinosis, blood vessel calcification), and cardiac arrhythmias due to hypercalcemia. It interacts with orlistat, cholestyramine and mineral oil, which drastically reduce its oral absorption.