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The Mechanism for Phenytoin (Dilantin) Associated Decreases in Vitamin D

Summary:

  • Vitamin D can come from one of three sources: sunlight exposure to uncovered skin, overt-the-counter (OTC) vitamin D supplements, and through foods.
  • Regardless of the source of vitamin D, none of them are active or able to directly modulate the absorption of calcium into the body and thus must become activated through at least two more steps with the first taking place in the liver and the second taking place in the kidney.
  • As it relates to patients taking phenytoin, it is known that these patients have lower levels of 25-hydroxyvitamin D levels and can begin to manifest as early as 60 days after starting phenytoin.
  • The mechanism for this reduction in 25-hydroxyvitamin D is due to phenytoin's ability to cause a dose-dependent inhibition of active calcium transport by intestinal epithelial cells (see figure provided).

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
August 2015

Explanation

  • Vitamin D is a well known fat soluble vitamin that is important for maintaining calcium and phosphate homeostasis, mineralization of the bone, and the modulation of gene expression, cell growth and differentiation.1-3   As it relates to calcium absorption from the gastrointestinal (GI) tract, vitamin D in the body must be activated before it can facilitate or increase GI absorption of calcium.1-4

    Vitamin D can come from one of three sources.1-3,5,6  The first occurs when the skin is exposed to sunlight.  Ultraviolet (UV) B radiation is able to penetrate exposed skin to facilitate the conversion of 7-dehydrocholesterol to previtamin D3 and then on to vitamin D3 or cholecalciferol.  The second way to get vitamin D is through over-the-counter (OTC) supplementation.  Most OTC products and some vitamin D fortified foods contain the same vitamin D3 or cholecalciferol formed from sun exposure.  The third way to get vitamin D is naturally through the diet.  As mentioned above, many vitamin D fortified foods will contain cholecalciferol.  However, plant based foods also contain vitamin D2 or what is also known as ergocalciferol.  It is important to note here that regardless of the source of vitamin D, none of them are active or able to directly modulate the absorption of calcium and thus must become activated through two more steps within the body.  This is best represented by the figure provided below.



    The first step in the process of activating either ergocalciferol or cholecalciferol takes place in the liver and is largely unregulated.4  A hydroxyl (-OH group) is added to carbon number 25 forming 25-hydroxyvitaminD or what is also known as calcidiol or 25-hydroxycholecalciferol.4  In the kidney, the newly formed 25-hydroxyvitamin D undergoes a second hydroxylation reaction on carbon number 1 to form 1,25-hydroxyvitamin D or what is also known as calcitriol or 1,25-dihydroxycholecalciferol (the active form of vitamin D).4   Depending on the level of regulation or the need for calcium in the blood, the 25-hydroxyvitamin D can be metabolized by 24-hydroxylase to form 24,25-dihdroxycholecalciferol (the inactive form).4

    As it relates to patients taking phenytoin, it is known that these patients have lower levels of 25-hydroxyvitamin D, which can begin to manifest as early as 60 days after starting phenytoin.7,8,9  The mechanism for this reduction in 25-hydroxyvitamin D is due to phenytoin's ability to cause a dose-dependent inhibition of active calcium transport by intestinal epithelial cells (see figure provided).10  As such patients being managed long-term on phenytoin for their epilepsy, should probably take 25-hydroxyvitamin D supplementation to avoid the risk for developing osteomalacia.8,9

    References:

    1. National Institutes of Health: Office of Dietary Supplements.  Dietary Supplement Fact Sheet: Vitamin D.  Last Accessed: June 10, 2011.  NIH-ODS
    2. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
    3. Cranney A, Horlsey T, O'Donnell S et al.  Effectiveness and safety of vitamin D in relation to bone health.  Evid Rep Technol Assess (Full Report)  2007;158:1-235.  
    4. DeLuca HF.  Metabolis and molecular mechanism of action of vitamin D: 1981.  Biochem Soc Trans  1982;10:147-158.  PubMed
    5. Holick MF.  Vitamin D deficiency.  N Engl J Med  2007;357(3):266-281.   
    6. Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr  2004;80:1710S-6S.  
    7. Gough H, Goggin T, Bissessar A et al, A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy.  Q J Med  1986;59:569-77.   
    8. Krishnamoorthy G, Nair R, Sundar U et al.  Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dosage: a prospective study.  Neurol India  2010;58:213-9.  
    9. Espinosa PS, Perez DL, Abner E et al.  Association of antiepileptic drugs, vitamin D, and calcium supplementation with bone fracture occurrence in epilepsy patients.  Clin Neurol Neurosurg  2011;113:548-51.  
    10. Von Borstel Smith M, Crofoot K, Rodriguez-Proteau R et al.  Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells.  Toxicol In Vitro  2007;21:855-62.

MESH Terms & Keywords

  • phenytoin, Dilantin, decrease, vitamin D, phenytoin and vitamin D, interaction, cholecalciferol, calciferol, D2, D3, vit D