Taken together, an unmet need clearly remains for identifying alternative immunosuppressive regimens that (1) maintain antirejection Glioma efficacy with substantially reduced CNI exposure; (2) optimize renal function, both short- and long-term, by minimizing CNI nephrotoxicity; (3) avoid or minimize CNI-associated adverse events; (4) reduce the recurrence of HCV and HCC; (5) reduce the occurrence of de novo posttransplant malignancies. The mammalian target of rapamycin (mTOR) inhibitors could potentially meet these criteria, in part because they allow the use of immunosuppressive regimens that include reduced doses of CNIs. The mTOR inhibitors also possess a mechanism of action that is different from other classes of immunosuppressants: sirolimus and everolimus engage FKBP12 to create complexes that engage and inhibit the target of rapamycin but cannot inhibit calcineurin (Figure 1).

Inhibition of the target of rapamycin blocks signal 3 by preventing cytokine receptors from activating the cell cycle [33]. In addition, mTOR inhibitors may promote tolerance through actions on regulatory T-cells and dendritic cells [34, 35]. Figure 1 Sites of action of immunosuppressive drugs (adapted from [33] with permission). Two mTOR inhibitors are currently approved for use in transplantation. Everolimus is approved by the FDA for renal and liver transplantation and by the EMA for renal, heart and liver transplantation (Certican and Zortress, Novartis Pharma AG; Basel, Switzerland) [36, 37].

Clinical experience with everolimus in liver transplantation is limited by the fact that it was only recently approved for liver transplantation and it was not approved for renal transplantation in the EU until 2003 and in the US until 2010. Sirolimus is approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for renal transplantation (Rapamune, Pfizer, NY, USA) [38, 39]. In the US, sirolimus was approved for renal transplantation in 1999. Although not approved for liver transplantation, it has still been used in several centres in liver transplant recipients. Everolimus is a derivative of sirolimus, differing by one extra hydroxyethyl group at position 40 [40]. In human studies, everolimus has a shorter half life (30 hours) compared to the 62 hours of sirolimus and a quicker time to steady state (4 days versus 6 days) [36, 38]. Both everolimus and sirolimus Drug_discovery are substrates in the p-glycoprotein and cytochrome P450-3A4 pathways [40, 41]. Therefore, the absorption and clearance of mTOR inhibitors may be influenced by drugs that affect cytochrome P450-3A4 and/or p-glycoprotein, including common drugs such as fluconazole, azithromycin, and protease inhibitors [36, 38, 39].