Clinical Immunosuppression using the Calcineurin-Inhibitors Ciclosporin and Tacrolimus

T cells play a key role in orchestrating the immune response to an allograft. The discovery of a potent and immunologically specific inhibitor of T cell activation, ciclosporin, dramatically improved the results of renal transplantation and transformed other types of organ transplantation from experimental to standard therapy. The discovery of a second drug, tacrolimus, that was structurally unrelated to ciclosporin but which had an identical mechanism of action, facilitated research which clarified the mechanisms underlying T cell activation. Although these drugs are powerful immunosuppressants, their clinical use is limited by their nephrotoxicity. In transplantation, this has led to their use in lower doses in combination with other immunosuppressive drugs. However long-term nephrotoxicity remains a significant problem, and this has curtailed the use of calcineurin-inhibitors for indications outside the field of transplantation. Ciclosporin and tacrolimus are metabolised by cytochrome P450 3A and are substrates for the P-glycoprotein transporter system. This results in complex pharmacokinetics with large variations in bioavailability and metabolism between individuals as well as a great number of clinically significant drug interactions. Therapeutic drug monitoring has been used to address these issues. For the foreseeable future, these powerful immunosuppressive agents are likely to continue to play a role in organ transplantation. However, newer immunosuppressants that are not nephrotoxic may begin to replace calcineurin-inhibitors for long-term maintenance therapy after transplantation.