**2.2. Tacrolimus (TRL)**

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

istic histologic changes observed on renal biopsy; these changes are usually progressive. Renal function should be monitored closely [23,24]. In systemic formulations hypertension occurred in 13% to 89% of patients receiving TRL in clinical trials. Antihypertensive therapy may be required. Potassium sparing diuretics, ACE inhibitors, and angiotensin receptor blockers should be used with careful consideration since due to the potential to cause hyperkalemia. Calcium channel blockers may be effective in treating TRL associated hypertension, but caution is warranted since interference with TRL metabolism may require a dosage reduction. [23,25]. Hyperlipidemia was reported as one of the more common adverse events in TRLtreated heart transplant recipients. Incidence: 10% to 34% [23]. In clinical trials tremor has occurred in 15% to 56% of patients receiving TRL [23,26]. In systemic formulations headache occurred in 24% to 64% of patients receiving TRL in clinical trials. Headache may respond to a dosage reduction [23]. In clinical trials hyperglycemia occurred in 21% to 70% of patients receiving TRL [23]. New onset diabetes mellitus has been reported in kidney, liver, and heart transplant patients receiving TRL therapy. Incidence: 11% to 22%. Close monitoring of blood

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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

MPA produces potent selective, noncompetitive, and reversible inhibition of inosine mono‐ phosphate dehydrogenase (IMPDH), an important enzyme in the *de novo* pathway of guanine nucleotide synthesis (Table 1). B and T lymphocytes are highly dependent on this pathway for cell proliferation, while other cell types can use salvage pathways; MPA therefore selectively inhibits lymphocyte proliferation and functions, including antibody formation, cellular adhesion, and migration [1,30]. *In vitro* and *in vivo* studies have demonstrated the ability of MPA to block proliferative responses of T and B lymphocytes, and inhibit antibody formation and the generation of cytotoxic T-cells [31]. In a preclinical study in mice, MPA increased survival of heart and pancreatic islet cell allografts. Studies in rats have also demonstrated prolonged heart allograft survival, as well as reversal of acute rejection and prevention of rejection in the sensitized animal. Antirejection effects have been attributed to decreased

The principal adverse effects of MPA are gastrointestinal, these include diarrhea, nausea and vomiting; hypertension; hematologic effects (anemia and leukopenia) and neurologic effects (anxiety asthenia dizziness headache insomnia tremor). There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus [1,33-35]. Diarrhea was

or enteric-coated mycophenolate sodium (Myfortic®) for kidney transplants [1,29].

glucose concentrations is recommended [23,27].

recruitment of activated lymphocytes to the graft site [32].

**2.3. Mycophenolic acid (MPA)**

*2.3.1. Mechanism of action*

*2.3.2. Side effects*

#### *2.2.1. Mechanism of action*

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].

#### *2.2.2. Side effects*

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 associated with TRL use [18].

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‐

istic histologic changes observed on renal biopsy; these changes are usually progressive. Renal function should be monitored closely [23,24]. In systemic formulations hypertension occurred in 13% to 89% of patients receiving TRL in clinical trials. Antihypertensive therapy may be required. Potassium sparing diuretics, ACE inhibitors, and angiotensin receptor blockers should be used with careful consideration since due to the potential to cause hyperkalemia. Calcium channel blockers may be effective in treating TRL associated hypertension, but caution is warranted since interference with TRL metabolism may require a dosage reduction. [23,25]. Hyperlipidemia was reported as one of the more common adverse events in TRLtreated heart transplant recipients. Incidence: 10% to 34% [23]. In clinical trials tremor has occurred in 15% to 56% of patients receiving TRL [23,26]. In systemic formulations headache occurred in 24% to 64% of patients receiving TRL in clinical trials. Headache may respond to a dosage reduction [23]. In clinical trials hyperglycemia occurred in 21% to 70% of patients receiving TRL [23]. New onset diabetes mellitus has been reported in kidney, liver, and heart transplant patients receiving TRL therapy. Incidence: 11% to 22%. Close monitoring of blood glucose concentrations is recommended [23,27].
