Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update

Abstract

This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can b...

Review on immunosuppression in liver transplantation

“…There are other presumed mechanisms for immunomodulator effects of this agent. MPA can inhibit monocyte chemoattraction, destroy activated lymphocytes and induce immune tolerance by affecting regulatory Tcell/helper Tcell balance [59] .…”

“…Higher doses may be required but are not usually recommended. There are also reports on the non-linear pharmacokinetics of MPA with decreasing the bioavailability of drug by increasing the dose [59] . The major adverse side effects of MPA are hematologic and gastrointestinal (GI).…”

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

“…As with other immunosuppressive agents, MMF has a significant adverse effect profile, including diarrhea, cytopenias (anemia and leukopenia) and increased risk of bacterial, pneumocystis and CMV infections [42]. MMF is used as part of the standard immunosuppressive regimen along with calcineurin inhibitors and steroids as an antiproliferative agent [33].…”

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

“…One kind of inhibitor, including 6-chloropurine riboside ribavirin and mizoribine, targets the binding pocket of the natural substrate, inosine monophosphate (IMP). Another kind of inhibitor (e.g., mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide) targets the site of the cofactor, NAD + / NADH, which usually leads to low selectivity or even side effects in clinical trials, such as diarrhea and leukopenia (10,11). Moreover, a third ligand has been speculated to bind to a possible site far from the IMP and NAD + pockets as an allosteric inhibitor.…”