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    Topical Tacrolimus
    S.J. Frankel, BSc and F.A. Kerdel, BSc, MBBS, MD
    Departments of Dermatology & Cutaneous Surgery,
    University of Miami School of Medicine, Miami, Florida, USA

      ABSTRACT
      Tacrolimus, available for intravenous, oral and now topical administration, is a potent immunosuppressive agent with the ability to block the production of Interleukin-2 (IL-2) and inhibit T-cell proliferation. Originally developed for use in organ transplantation, it is currently being studied for the treatment of inflammatory dermatoses. The US FDA recently approved tacrolimus ointment (Protopic, Fujisawa) for the treatment of atopic dermatitis. KEY WORDS: tacrolimus, atopic dermatitis, immunosuppressant

      Tacrolimus, previously known as FK506, is an 822-KDa-macrolide antibiotic produced by the fungus Streptomyces tsukubaensis. It is a powerful immunosuppressant and although itís not structurally related, tacrolimus exhibits selective antilymphocytic activity similar to cyclosporine, an agent that has revolutionized transplantation medicine and the treatment of selected autoimmune disorders. Currently, tacrolimus is emerging as a promising therapeutic alternative for the treatment of a number of dermatological diseases that have in common an aberrant immunologic response. This topical ointment is the first of its kind to be approved by the US FDA (December 2000), 0.1% for the treatment of moderate-to-severe atopic dermatitis in adults, and 0.03% for children older than 2 years of age and for adults who are undergoing long-term intermittent therapy. Phase III trials are underway in Canada, where a New Drug Submission (NDS) was put forward in July 2000. In Japan, Protopic 0.1% was approved in 1999.

      MECHANISM OF ACTION
      Both tacrolimus and cyclosporine interrupt the T-cell receptor mediated signal transduction pathway, which ultimately blocks the production of Interleukin-2 (IL-2) and inhibits T-lymphocyte proliferation. However, in vitro studies have shown that when compared to cyclosporine, tacrolimus exhibits 10-100 times greater immunosuppressive activity.1

      Unlike cyclosporine, a molecule which seems to be too large to penetrate human skin, tacrolimus is active topically and appears to target epidermal leukocytes, and antigen presenting epidermal dendritic cells.

      PHARMACOKINETICS
      When applied to intact human skin, in vitro studies have demonstrated that tacrolimus is not readily absorbed. However, on inflamed or damaged skin, it is absorbed in sufficient amounts to be topically active. The agent is metabolized in the liver by Cytochrome P4503A4 and is eliminated almost completely in the bile.1,3,5

      INDICATIONSs
      Perhaps most exciting is the finding that topical preparations of tacrolimus, in contrast to cyclosporine, are effective for the treatment of certain skin disorders including atopic dermatitis and allergic contact dermatitis.