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Chapter: Basic & Clinical Pharmacology : Immunopharmacology

Calcineurin Inhibitors - Immunosuppressive Agents

Cyclosporine (cyclosporin A, CSA) is an immunosuppressive agent with efficacy in human organ transplantation, in the treat-ment of graft-versus-host disease after hematopoietic stem cell transplantation, and in the treatment of selected autoimmune disorders.



Cyclosporine (cyclosporin A, CSA) is an immunosuppressive agent with efficacy in human organ transplantation, in the treat-ment of graft-versus-host disease after hematopoietic stem cell transplantation, and in the treatment of selected autoimmune disorders. Cyclosporine is a peptide antibiotic that appears to act at an early stage in the antigen receptor-induced differentiation of T cells and blocks their activation. Cyclosporine binds to cyclo-philin, a member of a class of intracellular proteins called immu-nophilins. Cyclosporine and cyclophilin form a complex that inhibits the cytoplasmic phosphatase, calcineurin, which is neces-sary for the activation of a T-cell-specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of inter-leukins (eg, IL-2) by activated T cells. In vitro studies have indi-cated that cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells, but it does not block the effect of such factors on primed T cells nor does it block interaction with antigen.

Cyclosporine may be given intravenously or orally, though it is slowly and incompletely absorbed (20–50%). The absorbed drug is primarily metabolized by the P450 3A enzyme system in the liver with resultant multiple drug interactions. This propensity for drug interaction contributes to significant interpatient variability in bioavailability, such that cyclosporine requires individual patient dosage adjustments based on steady-state blood levels and the desired therapeutic ranges for the drug. Cyclosporine ophthal-mic solution is now available for severe dry eye syndrome, as well as ocular graft-versus-host disease. Inhaled cyclosporine is being investigated for use in lung transplantation.

Toxicities are numerous and include nephrotoxicity, hyperten-sion, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. However, cyclosporine causes very little bone marrow toxicity. While an increased inci-dence of lymphoma and other cancers (Kaposi’s sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine, other immunosuppressive agents may also predis-pose recipients to cancer. Some evidence suggests that tumors may arise after cyclosporine treatment because the drug induces TGF-β, which promotes tumor invasion and metastasis.

Cyclosporine may be used alone or in combination with other immunosuppressants, particularly glucocorticoids. It has been usedsuccessfully as the sole immunosuppressant for cadaveric transplan-tation of the kidney, pancreas, and liver, and it has proved extremely useful in cardiac transplantation as well. In combination with methotrexate, cyclosporine is a standard prophylactic regimen to prevent graft-versus-host disease after allogeneic stem cell trans-plantation. Cyclosporine has also proved useful in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma. Its combination with newer agents is show-ing considerable efficacy in clinical and experimental settings where effective and less toxic immunosuppression is needed. Newer for-mulations of cyclosporine have been developed that are improving patient compliance (smaller, better tasting pills) and increasing bioavailability.


Tacrolimus (FK 506) is an immunosuppressant macrolide antibi-otic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidylprolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein(FKBP). Both complexes inhibit calcineurin, which is necessaryfor the activation of the T-cell-specific transcription factor NF-AT.

On a weight basis, tacrolimus is 10–100 times more potent than cyclosporine in inhibiting immune responses. Tacrolimus is utilized for the same indications as cyclosporine, particularly in organ and stem cell transplantation. Multicenter studies in the USA and in Europe indicate that both graft and patient survival are similar for the two drugs. Tacrolimus has proved to be effective therapy for preventing rejection in solid-organ transplant patients even after failure of standard rejection therapy, including anti-T-cell antibodies. It is now considered a standard prophylactic agent (usually in combination with methotrexate or mycophenolate mofetil) for graft-versus-host disease.

Tacrolimus can be administered orally or intravenously. The half-life of the intravenous form is approximately 9–12 hours. Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is potential for drug interactions. The dosage is determined by trough blood level at steady state. Its toxic effects are similar to those of cyclosporine and include neph-rotoxicity, neurotoxicity, hyperglycemia, hypertension, hyper-kalemia, and gastrointestinal complaints.

Because of the effectiveness of systemic tacrolimus in some dermatologic diseases, a topical preparation is now available. Tacrolimus ointment is currently used in the therapy of atopic dermatitis and psoriasis.

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