Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, UK
Pharmacotherapeutic group: vitamin D3 and analogues, colecalciferol
ATC Code: A11CC05
In its biologically active form vitamin D3 stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the biologically active form of vitamin D3. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active vitamin D3.
The pharmacokinetics of vitamin D3 is well known.
Vitamin D3 is well absorbed from the gastro-intestinal tract in the presence of bile, so the administration with the major meal of the day might therefore facilitate the absorption of vitamin D3.
It is hydroxylated in the liver to form 25-hydroxy-colecalciferol and then undergoes further hydroxylation in the kidney to form the active metabolite 1,25-dihydroxy-colecalciferol (calcitriol).
The metabolites circulate in the blood bound to a specific α – globin, vitamin D3 and its metabolites are excreted mainly in the bile and faeces.
A 57% lower metabolic clearance rate is reported in subjects with renal impairment as compared with that of healthy volunteers.
Decreased absorption and increased elimination of vitamin D3 occurs in subjects with malabsorption.
Obese subjects are less able to maintain vitamin D3 levels with sun exposure and are likely to require larger oral doses of vitamin D3 to replace deficits.
Pre-clinical studies conducted in various animal species have demonstrated that toxic effects occur in animals at doses much higher than those required for therapeutic use in humans.
In toxicity studies at repeated doses, the effects most commonly reported were increased calciuria and decreased phosphaturia and proteinuria.
Hypercalcaemia has been reported in high doses. In a state of prolonged hypercalcaemia, histological alterations (calcification) were more frequently borne by the kidneys, heart, aorta, testes, thymus and intestinal mucosa.
Colecalciferol (vitamin D3) has been shown to be teratogenic at high doses in animals.
At doses equivalent to those used therapeutically, colecalciferol (vitamin D3) has no teratogenic activity.
Colecalciferol (vitamin D3) has no potential mutagenic or carcinogenic activity.
Microcephaly, cardiac malformations and skeletal abnormalities were observed in the offspring. Offspring from pregnant rabbits treated with high doses of vitamin D had lesions anatomically similar to supravalvular aortic stenosis and offspring not showing such changes show vasculotoxicity similar to that of adults following acute vitamin D toxicity. Colecalciferol is also foetotoxic in mice with fewer and smaller offspring from pregnant mice receiving medium and high dose Vitamin D.
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