Immunophilin binders

Calcineurin inhibitors

The common target for cyclosporine and tacrolimus is calcineurin. After binding to cyclophillin (Cyp), cyclosporine interacts with calcineurin, inhibiting its catalytic domain. Thus dephosphorylation of transcription factors is prevented, as exemplified by the Nuclear Factor of Activated T- lymphocyte (NFAT), despite having a different ligand called FK binding protein (FKBP). Tacrolimus inhibits calcineurin in a similar way. Because phosphorylated transcription factors cannot cross the nuclear membrane, the production of key factors for activation and proliferation of T-helper cells (IL-2, TNFα, IFN-γ, and others) is reversibly inhibited.

The primary adverse effect for both these agents appears to be nephrotoxicity. Cyclosporine and tacrolimus decrease renal blood flow, which in turn can cause hypertension, fluid retention, hyperkalemia, and renal dysfunction.

Two types of renal dysfunction may result: functional toxicity is a reversible complication that improves when the drug is discontinued or the dose is lowered; chronic nephrotoxicity is characterized by interstitial fibrosis and arteriolar hyalinosis. Routine serum drug concentration monitoring is required when calcineurin inhibitors are used. Both drugs are metabolized in the P450-3A4 system; therefore, many drugs may interfere with their metabolism. Drugs reported to increase serum levels of both drugs include ketoconazole, erythromycin, fluconazole, diltiazem, and corticosteroids. Drugs that may decrease the blood levels of cyclosporine or tacrolimus include enzyme inducers such as anti-epileptic drugs (phenobarbital, phenytoin, carbamazepine) and the antibiotic rifampicin. Grapefruit juice increases the gastrointestinal absorption of cyclosporine.


Which of the following drugs is sometimes given with cyclosporin to reduce the costs of immunotherapy?


Which of the following best describes the side effects of cyclosporine therapy?