Pre-doxercalciferol


Pre-doxercalciferol is a precursor of doxercalciferol, a drug used for the treatment of secondary hyperparathyroidism and metabolic bone disease. Doxercalferol, the active ingredient of Hectorol®, is a synthetic vitamin D2 analog. Metabolic activation was carried out in vivo to form 1 α, 25-dihydroxyvitamin D2 (1 α, 25-(OH) 2D2), a naturally occurring, bioactive form of vitamin D2. Hectorol ®is available in the form of soft gelatin. The capsule contains 0.5 μ g or 2.5 μ g of dosier calcium alcohol. Each capsule also contains graded coconut oil, ethanol and butylhydroxyanisole (BHA) triglycerides. Capsule shell contains gelatin, glycerin, titanium dioxide and D & C yellow No.10 with or without FD&C red No. 40.

Doxercalferol is a colorless crystalline compound with a molecular weight of 412.66 and the molecular formula of C28H44O2. It is soluble in oil and organic solvents, but relative insoluble in water. In chemistry, doxercalferol is (1α, 3β, 5Z, 7E, 22E)-9, 10 secoergosta5, 7, 10 (19), 22- tetraene-1, 3-diol, and has the following structural formula:

Fig 1. Structure of doxercalferol and Pre-doxercalciferol

Mechanism of action

Calcitriol (1 α, 25-(OH) 2D3) and 1 α, 25-(OH) 2D2 regulate the level of blood calcium needed for the basic function of human body. Specifically, bioactive vitamin D metabolites control intestinal absorption of dietary calcium, tubular reabsorption of calcium by the kidney, and binding to parathyroid hormone (PTH) to mobilize calcium from bones. They directly act on bone cells (osteoblasts) to stimulate bone growth and on parathyroid gland to inhibit the synthesis and secretion of PTH (parathyroid hormone). These functions are mediated by the interaction of these bioactive metabolites with specific receptor proteins in different target tissues. In patients with chronic renal disease (CKD), lack of bioactive vitamin D metabolites (due to lack or deficiency of 25-hydroxyvitamin D-1-α-hydroxylase activity) leads to secondary hyperparathyropathy. This contributes to the development of metabolic bone disease.

Clinical Pharmacology

Vitamin D levels in the human body depend on two sources: (1) exposure to the sun’s ultraviolet rays converts 7-dehydrocholesterol in the skin into vitamin D 3 (cholecalciferol); (2) take vitamin D2 (ergocalciferol) or vitamin D3 from diet. Vitamin D2 and vitamin D3 must be metabolically activated in the liver and kidney before they can be fully activated in the target tissue. The first step in the activation process is to introduce a hydroxyl group into the side chain of C 25 through the liver enzyme CYP27, a vitamin D-25-hydroxylase. The products of the reaction are 25-(OH) D2 and 25-(OH) D3, respectively. Further hydroxylation of these metabolites occurs in the mitochondria of renal tissue and is catalyzed by renal 25-hydroxyvitamin D-1-α-hydroxylase to produce 1 α, 25-(OH) 2D2, the main bioactive form of vitamin D2, and 1 α, 25-(OH) 2D3 (calcitriol), the bioactive form of vitamin D3.

Indications and usage.

  • Dialysis patients:

Hectorol® is used to treat secondary hyperparathyropathy in dialysis patients with chronic renal disease. Before initiating, check iPTH, serum calcium and phosphorus. Check weekly thereafter until stable. Serum iPTH, calcium, phosphorus, and alkaline phosphatase should be monitored.

  • Pre-dialysis patients:

Hectorol® is used to treat secondary hyperparathyropathy in patients with stage 3 or stage 4 chronic renal disease. iPTH, serum calcium and phosphorus every 2 weeks for 3 months following initiation and dose adjustments, then monthly for 3 months, then every 3 months.

  • Contraindications.

Hectorol® is not used in patients with hypercalcemia or current evidence of vitamin D toxicity.

Common side effects

  • Headache, dizziness;
  • Nausea, vomiting;
  • Feeling short of breath;
  • Swelling; or general ill feeling.
  • Increased thirst or urination, or urinating less than usual;
  • Dryness or metallic taste in your mouth;
  • Itching, warmth, redness, tingly feeling;
  • Weakness, drowsiness, lack of energy, tired feeling;
  • Headache, dizziness, confusion, ringing in your ears;
  • Muscle weakness, bone pain;
  • Irregular heartbeats, feeling nervous or irritable.

References

1.Coburn, J. W., Maung, H. M., Elangovan, L., Germain, M. J., Lindberg, J. S., Sprague, S. M., … & Bishop, C. W. (2004). Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. American Journal of Kidney Diseases43(5), 877-890.

2. Li, J., Li, N., Yan, S., Liu, M., Sun, B., Lu, Y., & Shao, Y. (2018). Doxercalciferol Alleviates Bone Deteriorations and Cartilage Degeneration in Aging Mice. Experimental and Clinical Endocrinology & Diabetes.

Related Products

1β-doxercalciferol           trans-doxercalciferol        1, 3-bi-TBS-trans-Doxercalciferol

1α-Hydroxy VD4            1α-Hydroxy VD4           Vitamin D2 (Ergocalciferol)

25-Hydroxy-Ergocalciferol (25-(OH)-Vitamin D2)