Cyclosporin A Pharmacology And Mechanisms Of Action

Cyclosporin A is a neutral, cyclic undecapeptide derived from the soil fungus Tolypocladium inflatum gams. It is lipophilic and very hydrophobic so that it must be solubilized for clinical use. CyA can be administered intravenously or orally with a new microemulsion formulation which has proved to improve absorption and lower inter- and intrapatient variability of bioavailability [7], The drugs distributes widely in the circulation, it accumulates for 50-60% in red blood cells, and for 10-20% in leukocytes, and the remainder is bound to plasma lipoproteins. In healthy subjects the elimination half-life is approximately 6 h. CyA metabolism takes place in the liver thanks to the cytocrome P-450IIIA system: more than 30 metabolites are known, while it is matter of debate if some of them still have immunosuppressive or toxic properties. A major elimination pathway for this drug is biliary excretion. Drugs metabolized by the same enzymatic system affect cyclosporin concentration: with the inhibitors—such as ketoconozole, macrolide antibiotics, anphotericin B—the clearance of CyA it decreases, on the contrary it accelerates with the co-administration of P450 inductors—such as pheny-toin, rifampicine, trimethoprim-sulphamethoxazole and phenobarbital [8].

CyA binds to cyclophilin, a prolyl isomerase [9, 10], and after slightly restructuring its receptor to form an inhibitory complex, blocks the phosphatase action of calcineurin, which is an essential factor in the T-cell activation pathway. This block leads to the complete inhibition of the translocation of the cytoso-lic component of the nuclear factor of activated T cell (NF-AT), resulting in a failure to activate the genes regulated by NF-AT transcription factor such as IL-2, necessary for T-cell proliferation, and IL-4 and CD40 ligand, necessary for B-cell cooperation [11, 12]. Some evidence suggests that CyA may exert its immunosuppressive and anti-inflammatory action also independently from protein synthesis inhibition, i.e., preventing T-cell receptor-mediated exocitosis from cytotoxic T lymphocytes [13]. It is noteworthy that its global effects on lymphocytes is reversible. The most relevant adverse effect of CyA is renal toxicity which is a common cause of discontinuation both in post-transplant and autoimmune patients [14]. Other side effects can be hypertension, hepatotoxicity, hypertri-cosis, gingival hyperplasia, paresthesia, tremors and gastrointestinal discomfort.

CyA is devoid of myelotoxicity. Moreover experimental animal and human data support the CyA lack of genotoxicity [15].

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