**2.4. Sirolimus (SRL) and Everolimus (EVL)**

SRL(also known as Rapamycin and Rapamune®) is a macrocyclic lactone produced by the actinomycete *Streptomyces hygroscopicus*, with immunosuppressive, antitumor, and antifungal properties. SRL appears to be synergistic with CsA in kidney transplantation, but with a different side-effect profile. It is an immunosuppressive agent of potential benefit in clinical liver transplantation. EVL is an analogue of SRL with immunosuppressive and antiprolifera‐ tive activity. It is closely related chemically and clinically to SRL but has distinct pharmaco‐ kinetics. The main difference is a shorter half-life and thus a shorter time to achieve steady state concentrations of the drug [1,36].

#### *2.4.1. Mechanism of action of SRL*

SRL has been demonstrated to block the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation. Intracellularly, sirolimus forms a complex with cytosolic FK-binding proteins, primarily FKBP-12, considered essential for functionality; however, the sirolimus–FKBP-12 complex does not affect calcineurin activity. It binds to and inhibits a protein kinase, designated mammalian target of rapamycin (mTOR) (Table 1), which is a key enzyme in cell-cycle progression. Inhibition of mTOR blocks cell-cycle progression at the G1 to S phase transition [37,38]. Specific biochemical steps inhibited by SRL include activation of p70S6 kinase, activation of the cdk2/cyclinE complex, and phosphoryla‐ tion of retinoblastoma protein [37,38]. SRL appears to be less nephrotoxic than CsA and TRL; this may be related to its lack of effect on calcineurin [1,38]. In preclinical studies (*in vitro* and *in vivo*), additive or synergistic immunosuppressive effects were observed when SRL was combined with TRL, CsA, MMF, and brequinar [37].

#### *2.4.2. Side effects of SRL*

The use of SRL in renal transplant patients is associated with a dose-dependent increase in serum cholesterol and triglycerides that may require treatment. Other studies have identified hyperlipidemia and thrombocytopenia as significant SRL side effects [39]. In the other hand, while immunotherapy with SRL *per se* is not nephrotoxic, patients treated with CsA plus SRL have impaired renal function compared to patients treated with CsA and either azathioprine or placebo. Renal function therefore must be monitored closely in such patients. Other adverse effects include anemia, leukopenia, thrombocytopenia, hypokalemia or hyperkalemia, fever, and gastrointestinal effects. Delayed wound healing may occur with SRL use. As with other immunosuppressive agents, there is an increased risk of neoplasms, especially lymphomas, and infections [1,36,37].
