Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?

Abstract

Introduced in 1995, mycophenolate mofetil (MMF) would become the most powerful antiproliferative agent in the field of organ transplantation, thereby supplanting azathioprine, the first antiproliferative agent introduced in the early 1960s.Its association with tacrolimus greatly improved kidney transplant (KT) prognosis by significantly reducing the incidence of posttransplant acute rejection. MMF is also reputed to be a safe medication, but the frequency of the gastrointestinal complications associated with it, even minor ones, has induced the marketing of a second molecule called enteric-coated mycophenolate sodium. This late form of mycophenolate was supposed to be better tolerated thanks to its pharmacokinetic properties but the studies did not show significant differences between the two molecules. Otherwise, the combination of MMF with tacrolimus has significantly increased the risk of infections, particularly viral, and of neoplasia. To reduce this risk and avoid any situation of under or overexposure while remaining effective, only a strict and long-term monitoring of MMF allows the maintenance of already established therapeutic targets within the predefined ranges. In KT, individualizing the prescription and targets of MMF according to immunologic risk, global immunosuppression, and posttransplant period, as for other immunosuppressants, is open to discussion and may be beneficial.

Mycophenolic acid pharmacogenomics in kidney transplantation

“…Mycophenolic acid (MPA) is a potent antiproliferative drug broadly prescribed to prevent acute rejection in kidney transplantation. MPA is a reversible inhibitor of inosine-5´-monophosphate dehydrogenase (IMPDH), an important enzyme involved in the de novo synthesis of guanosine nucleotides, which are essential for the proliferation of T and B cells [1,2] . Consequently, guanosine nucleotide depletion by MPA prevents DNA replication, leads to repression of both cell-and humoral-mediated immunity and induces tolerance to allograft in kidney transplantation [1,3,4] .…”

“…MPA is a reversible inhibitor of inosine-5´-monophosphate dehydrogenase (IMPDH), an important enzyme involved in the de novo synthesis of guanosine nucleotides, which are essential for the proliferation of T and B cells [1,2] . Consequently, guanosine nucleotide depletion by MPA prevents DNA replication, leads to repression of both cell-and humoral-mediated immunity and induces tolerance to allograft in kidney transplantation [1,3,4] . IMPDH activity results from the expression of two isoforms, IMPDH type I and type II, which are encoded by IMPDH1 and IMPDH2, respectively [2] .…”

“…IMPDH activity results from the expression of two isoforms, IMPDH type I and type II, which are encoded by IMPDH1 and IMPDH2, respectively [2] . Both genes are constitutively expressed in most tissues, though activated T and B lymphocytes have a higher expression of IMPDH2 [1] . Also, IMPDH type II has a higher affinity for MPA compared to IMPDH type I, which makes it a selective and potent antiproliferative drug for T and B cells [1,3] [ Figure 1].…”

“…MPA is considered a safe drug even though some adverse events may occur, such as gastrointestinal complications, myelotoxicity, susceptibility to infections and neoplasms [1,3] . Designed to reduce gastrointestinal adverse events, the enteric-coated mycophenolate sodium salt (EC-MPS) has a delayed release formulation that delivers mycophenolate in the small intestine [7] .…”

“…MPAG excreted in the bile undergoes extensive enterohepatic recirculation, being hydrolyzed to MPA in the small intestine and reabsorbed [ Figure 1]. The enterohepatic recirculation contributes 10%-60% of the total MPA exposure and causes a secondary peak 6-12 h after oral MPA administration [1] . MPA is also eliminated in the urine as MPA in negligible amounts, and mostly as MPAG, possibly mediated by ABCC2 [19] .…”