**2.3. Mycophenolic acid (MPA)**

**2.2. Tacrolimus (TRL)**

312 Current Issues and Future Direction in Kidney Transplantation

*2.2.1. Mechanism of action*

*2.2.2. Side effects*

associated with TRL use [18].

TRL (Prograf®) is a macrolide antibiotic produced by *Streptomyces tsukubaensis*. It is practically insoluble in water. TRL is indicated for the prophylaxis of solid-organ allograft rejection in a manner similar to CsA. The recommended starting dose for TRL injection is 0.03 to 0.05 mg/kg per day as a continuous infusion. Recommended initial oral doses are 0.15 to 0.2 mg/kg per day for adult kidney transplant patients, in two divided doses 12 hours apart. These dosages are intended to achieve typical blood trough levels in the 5 to 15 ng/mL range. Pediatric

The compound is chemically distinct from CsA but both agents elicit similar immunosup‐ pressant effects. TRL suppresses both humoral (antibody) and cell-mediated immune re‐ sponses. Like CsA, TRL inhibits Tcell activation by inhibiting calcineurin [17]. The proposed mechanism for this effect is binding to an intracellular protein FK506-binding protein–12 (FKBP-12), immunophilin structurally related to cyclophilin. A complex of tacrolimus-FKBP-12, Ca2+, calmodulin, and calcineurin then forms, which inhibits the phosphatase activity of calcineurin (Table 1). As described for CsA the inhibition of phosphatase activity prevents dephosphorylation and nuclear translocation of NFAT and inhibits T-cell activation. Thus, although the intracellular receptors differ, CsA and TRL target the same pathway for immunosuppression [1,18]. The immunosuppressive activity of TRL is, however, more marked than that of CsA. Studies on cultured CD4+ (T-helper) lymphocytes have demonstrat‐ ed that TRL is at least 100 times more potent than CsA (weight basis) in selectively inhibiting secretion of various cytokines (i.e., interleukin-2, interleukin-3, interferon-gamma) [19,20]. The action of TRL on lymphocytes is more difficult to reverse than that of CsA; this may be attributable to the effect of TRL on impairing the expression of interleukin-2 receptors on alloantigen-stimulated T-cells [19]. TRL possesses another important effect in addition to the inhibition of IL-2 gene transcription, to be exact the ability to act as a general inhibitor of the protein secretory pathway, which strongly suggests that the diabetogenic effect of the TRL could be caused by the blockade of insulin secretion. This novel effect also provides an explanation for other side-effects observed in immunosuppressive treatment [1,21,22].

TRL is an established immunosuppressant for the prevention and treatment of allograft rejection in organ transplantation. However, TRL therapy also has several adverse effects like nephrotoxicity, hypertension, hyperkalemia, hyperglycemia, hyperlipidemia, neurotoxicity (tremor, headache, dizziness, seizure), gastrointestinal complaints, and diabetes are all

Nephrotoxicity has been reported with TRL therapy, particularly when used in high doses. Incidence: 36% to 59% [23]. Acute nephrotoxicity is characterized by an increased serum creatinine and/or a decrease in urine output, and is generally reversible. Chronic nephrotox‐ icity is associated with increased serum creatinine, decreased kidney graft life, and character‐

patients generally require higher doses than do adults [1,17].

MPA is a secondary metabolite produced by *Penicillium brevicompactum*, which has antibiotic and immunosuppressive properties used to prevent rejection of solid organ transplants [28]. It is highly soluble in aqueous media at physiological pH. The drug is marketed as the ester prodrug mycophenolate mofetil (CellCept®) (MMF) for kidney, liver, and heart transplants or enteric-coated mycophenolate sodium (Myfortic®) for kidney transplants [1,29].
