Alfacalcidol

Last updated
Alfacalcidol
Alfacalcidol.png
Alfacalcidol ball-and-stick.png
Names
Preferred IUPAC name
(1R,3S,5Z)-4-Methylidene-5-[(2E)-2-{{#parsoidfragment:0}}{(1R,3aS,7aR)-7a-methyl-1-[(2R)-6-methylheptan-2-yl]octahydro-4H-inden-4-ylidene}ethylidene]cyclohexane-1,3-diol
Other names
Alphacalcidol; 1-Hydroxycholecalciferol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.050.253 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C27H44O2/c1-18(2)8-6-9-19(3)24-13-14-25-21(10-7-15-27(24,25)5)11-12-22-16-23(28)17-26(29)20(22)4/h11-12,18-19,23-26,28-29H,4,6-10,13-17H2,1-3,5H3/b21-11+,22-12-/t19-,23-,24-,25+,26+,27-/m1/s1 Yes check.svgY
    Key: OFHCOWSQAMBJIW-AVJTYSNKSA-N Yes check.svgY
  • InChI=1/C27H44O2/c1-18(2)8-6-9-19(3)24-13-14-25-21(10-7-15-27(24,25)5)11-12-22-16-23(28)17-26(29)20(22)4/h11-12,18-19,23-26,28-29H,4,6-10,13-17H2,1-3,5H3/b21-11+,22-12-/t19-,23-,24-,25+,26+,27-/m1/s1
    Key: OFHCOWSQAMBJIW-AVJTYSNKBM
  • O[C@@H]1CC(\C(=C)[C@@H](O)C1)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(C)C)C
Properties
C27H44O2
Molar mass 400.64 g/mol
Melting point 136 °C (277 °F; 409 K)
0.016 g/100 mL
Pharmacology
A11CC03 ( WHO )
License data
Legal status
  • UK: POM (Prescription only) [1]
  • EU:Rx-only [2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Alfacalcidol (or 1-hydroxycholecalciferol) is an analogue of vitamin D used for supplementation in humans and as a poultry feed additive.

Contents

Alfacalcidol has a weaker impact on calcium metabolism [3] and parathyroid hormone levels [4] than calcitriol; but significant effects on the immune system, including regulatory T cells. [5] It is considered to be a more useful form of vitamin D supplementation, mostly due to its much longer half-life and lower kidney load. [6] It is the most commonly prescribed vitamin D metabolite for patients with end stage renal disease, given that impaired renal function alters the ability to carry out the second hydroxylation step required for the formation of the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3. Alfacalcidol is an active vitamin D3 metabolite, and therefore does not require the second hydroxylation step in the kidney. [7]

Mechanism of action

Action of alfacalcidol in vitamin D3 metabolism Alfacalcidol and D3-metabolism.svg
Action of alfacalcidol in vitamin D3 metabolism

Alfacalcidol is a prodrug that is rapidly metabolized in the liver to the active form, calcitriol. As it is already 1α-hydroxylated, it does not require activation in the kidney as cholecalciferol does. [8] After calcitriol binds to its intracellular receptor (vitamin D receptor, VDR), the synthesis of a calcium ion-binding protein increases. The compound enhances intestinal absorption of calcium and phosphate, regulates bone mineralization, and promotes calcium reabsorption in the renal tubules. [9]

Alfacalcidol prevents deficiency symptoms associated with impaired physiological 1α-hydroxylation of cholecalciferol or calcifediol in the kidneys, particularly in cases of chronic renal insufficiency. Alfacalcidol is not naturally present in the human body and is rapidly converted into calcitriol in the liver. [9]

Synthesis

The multi-step synthesis of alfacalcidol is illustrated in the following reaction sequence: [10] Synthesis of Alfacalcidol.svg

Properties

Alfacalcidol is practically insoluble in water, slightly soluble in 96% ethanol, and soluble in fatty oils. It is sensitive to air, heat, and light. In solution, a reversible isomerization to pre-alfacalcidol occurs, depending on temperature and duration. Both compounds are biologically active. [11]

History

Alfacalcidol was patented in 1971 and approved for medical use in 1978. [12]

Trade names

Pharmaceutical trade names include AlphaD and One-Alpha.

Other animals

Used as a poultry feed additive, it prevents tibial dyschondroplasia and increases phytate bioavailability. [13] [ original research? ]

References

  1. ↑ "One-Alpha Capsules - Summary of Product Characteristics (SmPC)". (emc). 9 November 2017. Retrieved 17 February 2021.
  2. ↑ "List of nationally authorised medicinal products" (PDF). ema.europa.eu. 11 February 2021. Retrieved 14 April 2023.
  3. ↑ Cavalli L, Cavalli T, Marcucci G, Falchetti A, Masi L, Brandi ML (May 2009). "Biological effects of various regimes of 25-hydroxyvitamin D3 (calcidiol) administration on bone mineral metabolism in postmenopausal women". Clinical Cases in Mineral and Bone Metabolism. 6 (2): 169–73. PMC   2781231 . PMID   22461169.
  4. ↑ Moe S, Wazny LD, Martin JE (2008). "Oral calcitriol versus oral alfacalcidol for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis: a randomized, crossover trial". The Canadian Journal of Clinical Pharmacology. 15 (1): e36-43. PMID   18192704. Archived from the original on 2014-10-06. Retrieved 2013-12-04.
  5. ↑ Zold E, Szodoray P, Nakken B, Barath S, Kappelmayer J, Csathy L, et al. (January 2011). "Alfacalcidol treatment restores derailed immune-regulation in patients with undifferentiated connective tissue disease". Autoimmunity Reviews. 10 (3): 155–62. doi:10.1016/j.autrev.2010.09.018. hdl: 2437/180066 . PMID   20868777.
  6. ↑ Nuti R, Bianchi G, Brandi ML, Caudarella R, D'Erasmo E, Fiore C, et al. (March 2006). "Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis". Rheumatology International. 26 (5): 445–53. doi:10.1007/s00296-005-0073-4. PMID   16283320. S2CID   9931256.
  7. ↑ Ritzerfeld M, Klasser M, Mann H (December 2001). "Alfacalcidol in the therapy of renal bone disease". International Journal of Clinical Pharmacology and Therapeutics. 39 (12): 546–50. doi:10.5414/cpp39546. PMID   11770836.
  8. ↑ G. Geisslinger, S. Menzel, T. Gundermann, B. Hinz, P. Roth (Hrsg.): Mutschler Arzneimittelwirkungen. 11. Auflage. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2020, S. 1148 ff.
  9. 1 2 Entry on Alfacalcidol . at: Römpp Online . Georg Thieme Verlag, retrieved {{{Datum}}}.
  10. ↑ Axel Kleemann, J. Engel, B. Kutscher, D. Reichert (2014-05-14), Pharmaceutical Substances, 5th Edition: Syntheses, Patents and Applications of the most relevant APIs, Georg Thieme Verlag, p. 32, ISBN   978-3-13-179525-0 {{citation}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Monographie „Alfacalcidol“, European Pharmacopoeia 10th Edition (Ph. Eur. 10.0), EDQM Council of Europe, 2019.
  12. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. XXX. ISBN   9783527607495.
  13. ↑ "Vitamin Derivatives". vitaminderivatives.com. Retrieved 14 April 2023.
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