Cyclosporine (and tacrolimus) prevents activation of T lymphocytes despite appropriate stimulation of T lymphocyte surface
receptors by antigen-derived peptides.1,2 These drugs bind to intracellular cyclophilin, producing a drug-protein complex that inactivates the enzyme calcineurin,
an inducer of the lymphocyte DNA transcription factor that, in turn, upregulates interleukin-2 (IL-2) production, the main
inducer of T cell proliferation. Calcineurin inhibition, therefore, prevents or slows clonal expansion of activated T cells
and blocks the downstream activation of B lymphocytes, macrophages, and cytotoxic T cells. Despite the theoretically broad
immunosuppressive effects of cyclosporine on much of the adaptive immune response, conflicting evidence as to its benefit
in canine IMHA combined with a much higher cost than that of prednisone has limited its use in most diseases to an adjunctive
treatment option rather than as a first-line agent.
Cyclosporine is metabolized primarily by enzymes of the cytochrome P-450 system. So any drug that inhibits, activates, or
competes for these enzymes will alter serum cyclosporine concentrations. For example, concurrent administration of phenobarbital,
a cytochrome P-450 enzyme inducer, results in lower than expected serum cyclosporine concentrations. On the other hand, ketoconazole
and erythromycin increase serum cyclosporine concentrations via cytochrome P-450 inhibition. This interaction can be exploited
in patients with severe cyclosporine-induced gastrointestinal tract signs or in cases in which drug cost is prohibitive; for
example, concurrently administering ketoconazole, a relatively inexpensive drug, allows a reduction in the cyclosporine dose.
However, ketoconazole coadministration is not routinely recommended because this drug may also result in hepatotoxicosis or
Cyclosporine pharmacokinetics is strongly influenced by drug administration in conjunction with a meal, diet composition,
and bioavailability of the drug formulation being administered.18 Most current formulations of cyclosporine are well-absorbed after oral administration, although nonaqueous formulations
(i.e. Sandimmune—Novartis) result in lower and less predictable serum concentrations when administered in an equivalent mg/kg dose.
Cyclosporine is fat-soluble, so having owners administer the drug with a meal may improve absorption, particularly if a patient
can also be appropriately fed a high-fat content diet. The therapeutic serum cyclosporine concentration cannot be predicted
purely based on mg/kg dosing, and regular measurement of the trough cyclosporine concentration is required. The trough concentration
(i.e. immediately before the next pill) can be measured as early as 48 hours after a change in drug dose, and many commercial laboratories
offer this assay. The target trough cyclosporine concentration for most immune-mediated diseases is 400 to 600 ng/ml.
Most published support for the use of systemic cyclosporine exists for dogs with perianal fistulae, IMHA, and immune-mediated
dermatologic diseases (Table 1); however, sporadic reports exist on the use of this drug for many other diseases. Glucocorticoids are rarely used as first-line
therapy for perianal fistulae since affected dogs often respond completely to cyclosporine, with permanent remission possible.19-21 Topical tacrolimus may also be used, although this drug can be toxic if licked and requires gloved application.22 Patients with perianal fistulae appear to require lower trough cyclosporine concentrations (100 to 300 ng/ml) than do dogs
with other diseases. Also, because larger breeds are more commonly affected, adjunctive therapy with ketoconazole is more
Dogs with IMHA that fail to respond to prednisone (with or without azathioprine) may benefit from cyclosporine as well. Although
a definitive benefit to cyclosporine has not been demonstrated in this disease,24 many internists report that some dogs will achieve disease remission with cyclosporine administration. If cyclosporine is
used to treat canine IMHA, avoid simultaneous administration of azathioprine because the cumulative immunosuppression anecdotally
increases the prevalence of opportunistic infections.
Cyclosporine is rarely used in cats with immune-mediated diseases despite the successful long-term immunosuppression regularly
achieved with this drug in feline renal transplant recipients. Use of cyclosporine has been sporadically reported in cats
with presumptively allergic or hypersensitivity-induced skin diseases (such as eosinophilic plaques or indolent ulcers) or
as a rescue agent in patients with severe, uncontrolled feline asthma complex, but whether this drug offers any advantages
over traditionally used glucocorticoids or alternative immunosuppressive agents is unknown.25,26 Absorption and systemic distribution of cyclosporine in cats does not appear to differ from that in dogs, with similar individual
animal variability.18 Unlike dogs, however, whole blood drug concentrations two hours after pill administration may be more accurate than trough
drug concentrations.27 Because of this uncertainty in the optimal timing for sample collection, in many cases changes in cyclosporine dose in cats
are dictated primarily by the patient's response to therapy.