Topical Vitamin D 3

Structure and Biosynthesis

Although provitamin D ₃ (7-dehydrocholesterol; Fig. 49.1 ) is found in plants and animals, dietary sources comprise less than 10% of the vitamin D requirement for most people. Only a few foods, such as oily fish and egg yolks, naturally contain Vitamin D ₃ . Additionally, milk, some juice products, and some breads and cereals are fortified with synthetically produced vitamin D ₂ (ergocalciferol). The skin has a large capacity to produce vitamin D, and exposure to ultraviolet B (UVB) light is still the most efficient mechanism for producing adequate amounts.

Q49.2 In the epidermis, provitamin D ₃ is cleaved by UVB light to form previtamin D ₃ (9,10-secosterol precholecalciferol), which is inert. Temperature-dependent isomerization of previtamin D ₃ then occurs, generating vitamin D ₃ (cholecalciferol) in the skin. Vitamin D ₃ is a very labile molecule, and may become inactivated if it does not promptly enter into the circulation. Once in circulation, vitamin D ₃ is transported to the liver, where it undergoes hydroxylation by the cytochrome P-450-dependent enzyme 25-hydroxylase to become 25-hydroxyvitamin D ₃ . In the kidney (as well as in other tissues such as placenta, pulmonary alveolar macrophages, and bone cells), 25-hydroxyvitamin D ₃ is hydroxylated by 1 α -hydroxylase to form calcitriol (1,25[OH] ₂ D ₃ ), the active hormone. 1α-Hydroxylation is the rate-limiting step in the biosynthesis of 1,25(OH) ₂ D ₃ , and the activity of this enzyme is tightly regulated by serum levels of calcium, phosphorus, parathyroid hormone, and 1,25(OH) ₂ D ₃ itself.

Recent studies in human keratinocytes have demonstrated that the keratinocyte is unique in that it contains all the necessary enzymes to convert 7-dehydrocholesterol to active calcitriol. Both 1 α -hydroxylase and 25-hydroxylase have been demonstrated in human keratinocytes, although their physiologic role is still unknown.

Metabolism

The active form of vitamin D, 1,25(OH) ₂ D ₃ , is metabolized by 24-hydroxylase to 1,24,25-trihydroxyvitamin D ₃ , which has very little biologic activity compared with the active form, 24-hydroxylase, which is expressed both in the kidney and in human skin. It is an inducible enzyme; topical application of calcitriol to human skin markedly enhances its activity.

Mechanism of Action

Q49.3 Vitamin D in the form of 1,25(OH) ₂ D ₃ acts mainly via the VDR to regulate cell proliferation, differentiation, and immune function, as well as calcium and phosphorus metabolism. The VDR protein belongs to the thyroid hormone, corticosteroid, and retinoic acid nuclear receptor gene family. When the VDR is activated by its ligand 1,25(OH) ₂ D ₃ or the synthetic analogs discussed in this chapter, the drug–receptor complex, in association with the retinoid X receptor-α (RXR-α) binds to specific deoxyribonucleic acid (DNA)-binding sites called vitamin D response elements, with subsequent induction or repression of the gene that contains these elements ( Fig. 49.2 ). Vitamin D inhibits proliferation of keratinocytes in culture and modulates epidermal differentiation. It promotes the formation of the cornified envelope by increasing gene expression and protein levels of involucrin, loricrin, filaggrin, and transglutaminase. Vitamin D has a number of effects on inflammatory markers and immunomodulators, although the physiologic significance of these effects is not fully understood. Vitamin D inhibits production of interleukin (IL)-2, IL-6, and interferon (IFN)-γ by T-helper (Th)1 cells, and IL-17 by Th17 cells. It also blocks transcription of granulocyte–macrophage colony-stimulating factor (GM-CSF) messenger ribonucleic acid (mRNA), and inhibits cytotoxic T-cell and natural killer cell activity. Conversely, vitamin D increases the activity of T regulatory cells and the production of IL-4 by Th2 cells. Additionally, vitamin D contributes to innate immune responses by inducing gene expression of cathelicidin and β-defensin.

Calcipotriene

Q49.4 Calcipotriene (calcipotriol) is a synthetic analog of calcitriol. It binds to the VDR with the same affinity as calcitriol, but is less likely to cause hypercalcemia, owing to its rapid local metabolism when applied topically. It is available under the trade names Dovonex cream (USA), Sorilux foam (USA), Calcitrene ointment (USA), Daivonex (Europe, Asia), Psorcutan (Europe), and Dermocal (South America). Only one small, short-duration study has directly compared ointment and cream formulations of calcipotriene; it found that the ointment formation resulted in significantly greater improvement in Psoriasis Area Severity Index (PASI) scores compared with the cream formulation.

Calcitriol

Calcitriol is the natural bioactive form of 1,25(OH) ₂ D ₃ . The drug is available for systemic administration (oral and intravenous routes). It is now available in the United States under the trade name Vectical as a 3 μg/g ointment topically applied twice daily for the treatment of psoriasis.

Tacalcitol

Tacalcitol (1α,24-dihydroxyvitamin D ₃ ) differs structurally from calcitriol in that there is a hydroxyl group at the 24-position, rather than at the 25-position. Like calcipotriene, it has less hypercalcemic activity than calcitriol. It was developed in Japan, where it is available as a 2 μg/g (0.0002%) ointment, cream, lotion, and solution, as well as a 20 μg/g (0.002%) ointment. In Europe, tacalcitol is available as a 4 μg/g (0.0004%) ointment for once-daily application in the treatment of psoriasis. It is not currently available in the United States.

Other Vitamin D Analogs

Studies are under way with other topical vitamin D analogs. Two that have undergone placebo-controlled, double-blind studies are topical maxacalcitol (1α,25-dihydroxy-22-oxacalcitriol) and hexafluoro-1,25-dihydroxyvitamin D ₃ . Both showed benefit in the treatment of psoriasis, and neither was associated with hypercalcemia. Neither is currently available in the United States.

US Food and Drug Administration-Approved Indication—Psoriasis