Immunosuppressants Pharmacogenomics

Abstract

This chapter will focus on three immunosuppressants used for posttransplantation graft maintenance. These include the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and the cell proliferation inhibitor sirolimus. These drugs share similar mechanism of action, metabolism pathway, and pharmacogenetics/pharma-cogenomics. Other immunosuppressants will not be discussed here. 16.1 Clinical Indication and Mechanism of Action Cyclosporine, tacrolimus (also named FK506), and sirolimus (also named rapamycin) are all used posttransplantation to suppress T-cell-mediated immune responses. They are frequently used in combination with steroids and antiproliferative agents such as azathioprine or mycophenolate mofetil. Tacrolimus has been shown to be 10–100 times more potent than cyclosporine [1, 2]. Both tacrolimus and sirolimus are used at much lower doses than cyclosporine. Two recent multisite randomized trials suggest that regimens containing low-dose cyclosporine or low-dose tacroli-mus are safe and effective, and in the case of tacrolimus, even more advantageous for renal function, allograft survival, and acute rejection rates in renal transplant recipients than standard-dose regimens [3, 4]. The target trough levels of 50–100 ng/mL cyclosporine and 3–7 ng/mL tacrolimus in these studies are much lower than the traditionally suggested target trough ranges. See Wallemacq et al. [5] for proposed target tacrolimus trough concentration guidelines for kidney, heart, and liver transplantation by the 2007 European Consensus Conference on Tacrolimus Optimization. Although chemically distinct, cyclosporine and tacrolimus both function at the same step in the immune activation cascade by blocking the serine/threonine phos-phatase activity of calcineurin [6]. The binding of foreign antigens to receptors on the T cell surface triggers the activation of ras and the increase in the intracellular calcium concentration. Through the facilitation of calcium/calmodulin, the phos-phatase activity of calcineurin is activated. Calcineurin then dephosphorylate NF-ATc, the cytosol subunit of the transcription factor NF-AT. Dephosphorylation triggers nuclear translocation of NF-ATc, which binds to NF-ATn and leads to transcription activation of cytokines and T-cell activation. Cyclosporine and tacroli-mus form complexes with their respective immunophilins, cyclophilin and FKBP12, which further engage calcium/calmodulin/calcineurin to form a pentamer and inhibit the phosphatase activity of calcineurin, thereby blocking T-cell activation and cytokine production. Sirolimus is structurally related to tacrolimus. It also binds to FKBP12, but inhibits mTOR (mammalian target of rapamycin), a key regulator of cell growth and proliferation. The cell cycle of various cell types are arrested in G1 phase as a result of mTOR inhibition [7]. The mechanism of action of the three drugs is depicted in Fig. 16.1. Fig. 16.1 Schematic drawing illustrating the mechanism of action for cyclosporine, tacrolimus, and sirolimus. CnA and CnB are the catalytic and regulatory subunits of calcineurin, respectively