Inosine monophosphate dehydrogenase (IMPDH); de novo purine synthesis

Inosine monophosphate dehydrogenase is a crucial enzyme that T and B lymphocytes use for the de novo production of guanosine nucleotides [1].

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Mycophenolic acid, the active metabolite of mycophenolate mofetil, is a non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH blocks the de novo synthesis of guanosine nucleotides which are necessary substrates for DNA and RNA synthesis. Unlike other cell types which can use the salvage pathway, B and T lymphocytes are dependent upon the de novo pathway for the generation of guanosine. Data from in vitro studies indicate that mycophenolic acid and/or mycophenolate mofetil inhibit mixed lymphocyte responses and human peripheral blood lymphocyte proliferation induced by a variety of mitogens and antigens. Mycophenolic acid decreases intracellular pools of guanosine triphosphate (GTP) and deoxyguanosine triphosphate (dGTP) in mitogen-stimulated human peripheral blood monocytes or T lymphocytic cell lines but has no effect on GTP concentrations in human neutrophils [2].

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Aims: Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection.
Methods: Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa.
Results: We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1β, tumour necrosis factor-α and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-α but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine.
Conclusions: Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions [4].

In an ACI-to-Lewis rat heterotopic cardiac transplant model, treatment of Mycophenolate mofetil at doses of 20 mg/kg and 40 mg/kg leads to a prolongation of graft survival, with median survival time (MST) of 14.5 days and 18.5 days, respectively. In bleomycin (BLM)-induced scleroderma mouse model, Mycophenolate mofetil reduces inflammatory-cell infiltration, tissue hydroxyproline content and dermal thickness.

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Mycophenolate mofetil has been shown to have efficacy in several animal models of transplantation (including cardiac, hepatic, pancreatic islet and renal). Mycophenolate mofetil was effective in preventing rejection or reversing ongoing rejection in rodent cardiac and canine renal allograft transplantation. However, the drug was only marginally effective in concordant and was ineffective in discordant cardiac xenograft transplantation. In the rat renal allograft model, mycophenolate mofetil effectively attenuated functional, morphological and immunohistological changes (significant reductions in proteinuria, glomerulosclerosis, arterial obliteration, macrophage and lymphocyte infiltration and expression of adhesion molecules and cytokines) associated with chronic rejection. The drug has also been shown to inhibit antibody production in rats and in humans. In rodent studies, mycophenolate mofetil was associated with the induction of donor-specific tolerance to grafted atrial tissue after cardiac allograft transplantation and to grafted thyroid tissue or injected spleen cells after pancreatic islet allograft transplantation [2].

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Mycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an important enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or mycophenolic acid inhibit the proliferation of lymphocytes and the production of antibodies induced by a variety of mitogens and antigens. Mycophenolate mofetil is also active in several animal models of transplantation and has produced effects in animals that indicate that it may inhibit the chronic rejection process. Mycophenolate mofetil has been compared with azathioprine or placebo in 3 large, randomised, double-blind, multicentre trials as part of combination immunosuppression therapy with cyclosporin and corticosteroids. Compared with either placebo or azathioprine (1 to 2 mg/kg/day or 100 to 150 mg/day), mycophenolate mofetil 2 or 3 g/day was associated with a significantly lower proportion of patients experiencing acute rejection or treatment failure during the first 6 months after transplantation. Mycophenolate mofetil also tended to be associated with a lower proportion of patients who required a full course of antirejection therapy. However, the proportion of patients who died or who had graft loss was similar between all of the treatment groups. There are currently no data regarding the effects of mycophenolate mofetil on long term patient or graft survival, which are important clinical outcomes in assessing its place in the management of renal transplantation. Clinical trials are also needed to evaluate mycophenolate mofetil in specific patient populations (e.g. repeat renal transplant patients or highly sensitised patients), to determine its efficacy in alternative immunosuppressive protocols and to investigate its use in the transplantation of other solid organs. In summary, mycophenolate mofetil appears to be an attractive new agent in the prevention of graft rejection in renal transplant recipients that has shown superior efficacy to azathioprine. Although long term clinical outcome data are required, mycophenolate is a potentially important advance in transplant immunosuppression [2].

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Background: T lymphocytes induce the transformation of fibroblasts into myofibroblasts, the main mediators of fibrogenesis. The inosine 5'-monophosphate dehydrogenase inhibitor mycophenolate mofetil (MMF) and the anti-CD25 monoclonal antibody daclizumab (DCZ) have been reported to suppress the proliferation of T lymphocytes.
Aim: To evaluate the preventive effects of MMF and DCZ in early stages of bleomycin (BLM)-induced scleroderma.
Methods: This study involved five groups of Balb/c mice (n = 10 per group). Mice in four of the groups were injected subcutaneously (SC) with BLM [100 μg/day in 100 μL phosphate-buffered saline (PBS)] for 4 weeks; the remaining (control) group received only 100 μL PBS. Three of the BLM-treated groups also received either intraperitoneal MMF 50 or 150 mg/kg/day, or SC DCZ 100 μg/week. At the end of the fourth week, all mice were killed, and blood and tissue samples were obtained for further analysis.
Results: In the BLM-treated group, increases were seen in inflammatory-cell infiltration, α-smooth muscle actin-positive (α-SMA+) fibroblastic cell count, tissue hydroxyproline content, and dermal thickness. Dermal fibrosis was histopathologically prominent. In BLM-treated mice also given MMF or DCZ, inflammatory-cell infiltration, tissue hydroxyproline content and dermal thickness were decreased. In the MMF groups, decreases were also noted in α-SMA+ fibroblastic cell count.
Conclusion: In this BLM-induced dermal fibrosis model, MMF and DCZ treatments prevented the development of dermal fibrosis. Further studies are needed to evaluate whether targeting T lymphocytes is effective in resolving pre-existing fibrosis in human scleroderma [5].

Analyses of microglial and astrocytic apoptosis and proliferation [4]
Microglial cells or astrocytes treated with Mycophenolate MofetilMMF or incubated in culture medium were used to determine the possible toxic concentration range of Mycophenolate Mofetil/MMF. Apoptotic cells were visualized by immunocytochemical demonstration of activated caspase-3. Proliferation studies on microglial cells were performed in astrocyte/microglial cell co-cultures because significant microglial proliferation was only obtained in the presence of astrocytes. Stimulation of isolated microglial cells with LPS or macrophage-colony stimulating factor alone did not induce significant proliferative activity (data not shown). To analyse proliferation of microglial cells bromo-desoxy-uridine (BrdU; 0.01 mM) was added to the culture medium for 16 h prior to fixation. Foetal calf serum (1–10%) or corticotrophin releasing factor (CRF, 10 µM) for 48 h were used to stimulate proliferation in isolated astrocyte cultures, and BrdU (0.01 mM) was added 16 h prior to fixation. The proliferation index was calculated as the percentage of proliferating cells related to the total number of cells.

Animals and experimental protocols [5]
Fifty specific‐pathogen‐free female Balb/c mice, 6 weeks old and weighing 20–25 g, were used for the experimental procedures.
Defined areas of the lower back skins of the mice were shaved for subcutaneous injections. Mice in the control group received 100 μL/day phosphate‐buffered saline (PBS) subcutaneously (SC) to the shaved back skin. To induce dermal fibrosis, the remaining four groups received BLM 100 μg dissolved in 100 μL PBS and sterilized by filtration (0.2 μm filter) to the shaved skin on the back. Two groups of these BLM‐treated mice were also injected either intraperitoneally with MMF 50 or 150 mg/kg/day dissolved in 100 μL and 300 μL saline containing 0.4% Tween 80 and 0.9% benzyl alcohol, respectively, and a third BLM‐treated group was given DCZ 100 μg (100 μL) SC once weekly.

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Dissolved in 0.5% methylcellulose water; 40 mg/kg; i.v. administration
Lewis rats with abdominal vascularized heterotopic cardiac transplantation

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Clinical Efficacy [2]
Initial noncomparative trials helped to determine the efficacy of mycophenolate mofetil and provided the appropriate dosage regimens for use in larger clinical trials. Three randomised, double-blind, multicentre trials have been conducted comparing mycophenolate mofetil with either placebo or azathioprine as part of combination therapy (with cyclosporin and corticosteroids) for the prevention of renal transplant rejection. Acute rejection or treatment failure (premature withdrawal from the study for any reason) during the first 6 months after transplantation occurred in significantly fewer patients receiving mycophenolate mofetil 2 or 3 g/day (range 30.3 to 38.8%) than either placebo (56.0%), or azathioprine 1 to 2 mg/kg/day (47.6%) or 100 to 150 mg/day (50%). The proportion of patients who required full courses of antirejection therapy (corticosteroids and/or anti-lymphocyte therapy) during the first 6 months post-transplant also tended to be lower in patients who received mycophenolate mofetil (range 21.1 to 31%) than either placebo (51.8%) or azathioprine (44.5 and 46%) recipients although the differences were not statistically significant. There were no differences between any of the treatment groups in terms of graft loss or patient survival at 6 or 12 months. There are currently no data on the effect of mycophenolate mofetil on long term patient or renal graft survival. Subgroup analysis of one multicentre study revealed that African-Americans receiving mycophenolate mofetil 3 g/day tended to have a lower rate of biopsy-proven acute rejection and/or treatment failure than those receiving 2 g/day. The use of mycophenolate mofetil in children is limited to a single report involving 14 patients. Data regarding the use of mycophenolate mofetil in the treatment of acute rejection are limited but initial results are promising. In patients with biopsy-proven rejection, mycophenolate mofetil 3 g/day was associated with a significantly lower frequency of subsequent biopsy-proven rejection or treatment failure than high dose intravenous corticosteroids (29 vs 51%).

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Dosage and Administration [2]
The initial recommended dosage of mycophenolate mofetil for the prevention of renal transplant rejection is lg twice daily to be initiated within 72 hours of transplantation as part of a combination regimen with cyclosporin and corticosteroids. Although dosages of up to 3 g/day have been used, they were less well tolerated than 2 g/day and there was no difference in clinical efficacy between these dosages. In patients with glomerular filtration rate <25 ml/min (1.5 L/h)/ 1.73m dosages should not exceed 2 g/day. Dosage adjustments in patients with delayed graft function are not required.

Absorption, Distribution and Excretion
Mycophenolate mofetil is rapidly absorbed in the small intestine. Peak plasma concentrations of its active metabolite, mycophenolate mofetil (MPA), are reached 60 to 90 minutes after oral administration. A pharmacokinetic study in 12 healthy subjects showed a mean bioavailability of 94% for orally administered mycophenolate mofetil. In healthy volunteers, the peak plasma concentration (Cmax) of mycophenolate mofetil was 24.5 (±9.5) μg/mL. In kidney transplant recipients, Cmax was 12.0 (±3.82) μg/mL 5 days post-transplantation, increasing to 24.1 (±12.1) μg/mL 3 months post-transplantation. The AUC value after a single dose in healthy volunteers was 63.9 (±16.2) μg•h/mL, and the AUC values at 5 days and 3 months after kidney transplantation were 40.8 (±11.4) μg•h/mL and 65.3 (±35.4) μg•h/mL, respectively. Food does not affect the absorption of mycophenolate mofetil. A small amount of the drug is excreted in the urine as MPA (less than 1%). A pharmacokinetic study showed that after oral administration of mycophenolate mofetil, 93% was excreted in the urine and 6% in the feces. Approximately 87% of the administered dose is excreted in the urine as the inactive metabolite MPAG. The volume of distribution of mycophenolate mofetil is 3.6 (±1.5) to 4.0 (±1.2) L/kg. The plasma clearance of oral mycophenolate mofetil is 193 mL/min, and that after intravenous administration is 177 (±31) mL/min.
Absorption is rapid and extensive after oral administration.
In 12 healthy volunteers, the mean absolute bioavailability (based on MPA AUC) of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil was 94%. In kidney transplant patients receiving multiple mycophenolate mofetil treatments, the area under the plasma concentration-time curve (AUC) of MPA appeared to increase in a dose-proportional manner, up to a maximum daily dose of 3 g.
Protein binding: High binding to plasma albumin (97% binding of MPA to plasma albumin within the concentration range typically observed in stable kidney transplant patients). At higher mycophenolate glucuronide (MPAG) concentrations (e.g., in patients with impaired renal function or delayed recovery of transplanted kidney function), MPA binding may be reduced due to competition for binding sites between MPA and MPAG. In 12 healthy volunteers, the mean (± standard deviation) apparent volume of distribution of MPA after intravenous and oral administration was approximately 3.6 (±1.5) L/kg and 4.0 (±1.2) L/kg, respectively. At clinically relevant concentrations, MPA bound to plasma albumin was 97%. Within the range of MPAG concentrations typically observed in stable renal transplant patients, MPAG bound to plasma albumin was 82%; however, at higher MPAG concentrations (seen in patients with impaired renal function or delayed recovery of renal transplant function), MPA binding may be reduced due to competition for protein binding sites between MPAG and MPA. The mean plasma radioactivity ratio was approximately 0.6, indicating that MPA and MPAG are not widely distributed into the cellular components of the blood. For more complete data on the absorption, distribution, and excretion of mycophenolate mofetil (9 in total), please visit the HSDB record page.

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Metabolism/Metabolites
After oral and intravenous administration, mycophenolate mofetil is completely metabolized by hepatic carboxylesterases 1 and 2 to the active parent drug mycophenolic acid (MPA). Subsequently, it is metabolized by glucuronyltransferase to produce the inactive MPA phenol glucuronide (MPAG). This glucuronide metabolite is important because it is subsequently converted to MPA via enterohepatic circulation. Mycophenolate mofetil (MMF), which is not metabolized in the intestine, enters the liver via the portal vein and is converted to pharmacologically active MPA within hepatocytes. N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and their N-oxide moieties are other metabolites produced by the metabolism of MMF in the intestine by hepatic carboxylesterase 2. UGT1A9 and UGT2B7 in the liver are the main enzymes for MPA metabolism; in addition, other UGT enzymes are involved in MPA metabolism. The four major metabolites of mycophenolic acid (MPA) are: 7-O-MPA-β-glucuronide (MPAG, inactive), MPA acylglucuronide (AcMPAG) produced by uridine diphosphate glucuronyltransferase (UGT), 7-O-MPA glucoside produced by UGT, and a small amount of 6-O-demethyl-MPA (DM-MPA) produced by CYP3A4/5 and CYP2C8 enzymes. After oral and intravenous administration, mycophenolic esters are completely metabolized to the active metabolite MPA (mycophenolic acid). After oral administration, MPA metabolism occurs in the first-pass phase. MPA is mainly metabolized by glucuronyltransferase to produce the pharmacologically inactive MPA phenolglucuronide (MPAG). In vivo, MPAG is converted to MPA via enterohepatic circulation. Following oral administration of mycophenolate moiety to healthy subjects, the following metabolites of the 2-hydroxyethylmorpholine moiety were also detected in urine: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and N-oxide of N-(2-hydroxyethyl)-morpholine.
Biological half-life
The mean apparent half-life of mycophenolate moiety after oral administration was 17.9 (±6.5) hours, and after intravenous administration it was 16.6 (±5.8) hours.
Mycophenolic acid (MPA): Mean apparent half-life: approximately 17.9 hours after oral administration and approximately 16.6 hours after intravenous administration.
The mean (±SD) apparent half-life and plasma clearance of MPA after oral administration were 17.9 (±6.5) hours and 193 (±48) mL/min, respectively. After intravenous administration, its absorption time was 16.6 (±5.8) hours and the flow rate was 177 (±31) mL/min.

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Pharmacokinetic characteristics[2]
Mycophenolate mofetil is well absorbed after oral administration and is rapidly converted to the active metabolite mycophenolic acid. The area under the plasma concentration-time curve (AUC) is generally proportional to the dose; however, there are some differences in AUC values among different patients. The AUC and peak plasma concentration (Cmax) of mycophenolic acid in patients with stable renal transplantation (>3 months post-transplantation) are about 50% higher than those in patients in the early post-transplantation period.
Mycophenolic acid is mainly excreted in the urine as mycophenolic acid glucuronide (about 87%); 6% is excreted in the feces. After oral administration, the mean apparent half-life and plasma clearance of mycophenolic acid are 17.9 hours and 11.6 L/h, respectively.
After a single dose, the AUC of mycophenolic acid and its glucuronide metabolites was higher in patients with renal impairment than in patients with normal renal function. However, the pharmacokinetics of mycophenolic acid esters were not altered in patients with cirrhosis after a single dose. Data in children are limited, but the AUC and Cmax of mycophenolic acid appear to increase with age.

Protein Binding
Mycophenolic acid (a metabolite of mycophenolic acid esters) has a protein binding rate of 97%, primarily binding to albumin. Its inactive metabolite, MPAG, binds to plasma albumin at normal therapeutic concentrations at 82%. When MPAG concentrations are elevated due to various reasons such as renal impairment, the protein binding rate of MPA may decrease due to competitive binding. Mycophenolic acid esters (morpholinoethyl ester of mycophenolic acid) inhibit de novo purine synthesis by inhibiting inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effect involves T cells and B cells, preventing antibody formation. Mycophenolic acid esters have immunosuppressive effects when used alone, but are most commonly used in combination with other immunosuppressants. Mycophenolic acid esters in combination with cyclosporine and glucocorticoids have been studied in large randomized clinical trials involving nearly 1500 kidney transplant recipients. These trials showed that mycophenolic acid esters were significantly more effective than placebo or azathioprine in reducing treatment failure rates and the incidence of acute rejection. Furthermore, mycophenolate mofetil may help reduce the incidence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse reaction is gastrointestinal intolerance; hematological abnormalities have also been observed. The reversible cytosolic effect of mycophenolate mofetil allows for dose adjustment or discontinuation, thus avoiding serious toxicity or excessive suppression of the immune system. The occurrence of cytomegalovirus-induced tissue invasive disease and malignancy is an issue that needs to be evaluated through long-term follow-up studies. Mycophenolate mofetil does not cause the side effects common to other commercially available immunosuppressants, such as nephrotoxicity, hepatotoxicity, hypertension, neurological disorders, electrolyte disturbances, skin diseases, hyperglycemia, hyperuricemia, hypercholesterolemia, dyslipidemia, and bone loss. Based on preliminary information, the benefit-risk ratio of mycophenolate mofetil for preventing rejection in deceased kidney transplants has been confirmed to be positive. Data from studies on other types of organ transplantation are encouraging, but limited in number and insufficient to draw definitive conclusions. Long-term follow-up studies are needed to confirm these observations. Despite its high price, mycophenolate mofetil's benefits in reducing rejection, treatment failure, and associated costs suggest it may be cost-effective. [1]

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Tolerability [2]
The incidence of adverse events associated with mycophenolate mofetil appears to be dose-related: 2 g/day is generally better tolerated than 3 g/day. The most common adverse events include gastrointestinal adverse events (diarrhea, vomiting), hematologic and lymphatic adverse events (leukopenia, anemia), and infectious adverse events (sepsis, opportunistic infections). Patients receiving mycophenolate mofetil had a slightly higher incidence of diarrhea and sepsis (most commonly cytomegalovirus viremia) compared to those receiving azathioprine. The proportion of patients receiving 3 g/day of mycophenolate mofetil also increased compared to those receiving azathioprine. The overall risk of malignant tumors associated with mycophenolate mofetil is similar to that of azathioprine.

[1]. Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection. Drug Saf. 1997;17(2):75-92.

[2]. Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs. 1996;51(2):278-298.

[3]. Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection. Int Immunopharmacol, 2010. 10(1): p. 91-7.

[4]. Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil. Neuropathol Appl Neurobiol, 2010. 36(7): p. 598-611.

[5]. Mycophenolate mofetil and daclizumab targeting T lymphocytes in bleomycin-induced experimental scleroderma. Clin Exp Dermatol, 2012. 37(1): p. 48-54.

Mycophenolate mofetil (MMF) is a carboxylic acid ester formed by the condensation of the carboxylic acid group of mycophenolic acid with the hydroxyl group of 2-(morpholino-4-yl)ethanol. In the liver, it is metabolized to mycophenolic acid, an immunosuppressant, while mycophenolate mofetil is its prodrug. It is widely used to prevent tissue rejection after organ transplantation and to treat certain autoimmune diseases. It has multiple functions, including immunosuppression, prodrug, EC 1.1.1.205 (IMP dehydrogenase) inhibitor, and anticoronavirus drug. It is a γ-lactone, belonging to the phenolic class of compounds, and is also an ether, carboxylic acid ester, and tertiary amine compound. Its function is related to mycophenolic acid and 2-(morpholino-4-yl)ethanol. Mycophenolate mofetil (MMF, trade name CellCept) is a prodrug of mycophenolic acid and belongs to the class of reversible inosine monophosphate dehydrogenase (IMPDH) inhibitors. This drug is an immunosuppressant and is often used in combination with drugs such as cyclosporine and corticosteroids to prevent organ rejection after liver, kidney, and heart transplantation. Manufactured by Roche Pharmaceuticals, it was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the prevention of transplant rejection. In addition to the above uses, mycophenolate mofetil (MMF) has been investigated for the treatment of nephritis and other complications of autoimmune diseases. Unlike another class of immunosuppressants—calcineurin inhibitors—MMF generally does not cause nephrotoxicity or renal fibrosis. Previously, mycophenolic acid (MPA) was used to treat autoimmune diseases since the 1970s, but its use was discontinued due to its gastrointestinal side effects and carcinogenicity. To avoid the gastrointestinal side effects caused by MPA, a novel semi-synthetic MPA, 2-morpholine ethyl ester, was synthesized. Compared to MPA, this compound has higher bioavailability, stronger efficacy, and fewer gastrointestinal side effects. Mycophenolate mofetil is the morpholine ethyl ester of mycophenolic acid (MPA) and has potent immunosuppressive effects. Mycophenolate mofetil inhibits the proliferation of T cells and B cells by selectively inhibiting the de novo purine synthesis pathway. In vivo, its active metabolite, MPA, reversibly inhibits inosine 5'-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Mycophenolic acid (MPA) exhibits high lymphocyte specificity and cytotoxicity because activated lymphocytes are more dependent on salvage and de novo synthesis of guanine nucleotides than other cell types. (NCI04)
Mycophenolic acid is a compound derived from Penicillium lyssum and its close relatives. It blocks the de novo synthesis of purine nucleotides by inhibiting inosine monophosphate dehydrogenase (IMP dehydrogenase). Mycophenolic acid has selective effects on the immune system, inhibiting the proliferation of T cells and lymphocytes, as well as antibody production by B cells. It may also inhibit the recruitment of leukocytes to sites of inflammation.
See also: Mycophenolic acid (with active moiety); Mycophenolate hydrochloride (in salt form).
Indications
Mycophenolate hydrochloride is used in combination with other immunosuppressants to prevent rejection after kidney, heart, or liver transplantation in adults and children ≥3 months of age. Mycophenolate mofetil can also be used as a second-line treatment for autoimmune hepatitis that has failed first-line therapy, which is considered off-label use. Other off-label uses of this drug include the treatment of lupus-associated nephritis and dermatitis in children.
FDA Label
CellCept (CellCept), used in combination with cyclosporine and corticosteroids, is indicated for the prevention of acute transplant rejection in patients who have received allogeneic kidney, heart, or liver transplants.
Myfenax (Myfenax), used in combination with cyclosporine and corticosteroids, is indicated for the prevention of acute transplant rejection in patients who have received allogeneic kidney, heart, or liver transplants.
Myclausen (Myclausen), used in combination with cyclosporine and corticosteroids, is indicated for the prevention of acute transplant rejection in patients who have received allogeneic kidney, heart, or liver transplants.
Teva (Mycophenolate mofetil), used in combination with cyclosporine and corticosteroids, is indicated for the prevention of acute transplant rejection in patients who have received allogeneic kidney, heart, or liver transplants.

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Mechanism of Action
Mycophenolate mofetil's active metabolite, mycophenolic acid, inhibits the proliferation of T cells and B cells, as well as the production of cytotoxic T cells and antibodies. Mycophenolic acid prevents lymphocytes and monocytes from adhering to vascular endothelial cells (often part of inflammation) by glycosylating cell adhesion molecules. Mycophenolic acid inhibits de novo purine synthesis (thus promoting immune cell proliferation) by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), particularly preferentially inhibiting IMPDH II. IMPDH normally converts inosine monophosphate (IMP) to xanthine monophosphate (XMP), a key metabolite in the synthesis of guanosine triphosphate (GTP). GTP is an important molecule in the synthesis of ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and proteins. Due to the above series of effects, mycophenolate mofetil reduces the de novo synthesis of guanosine nucleotides, thereby interfering with the synthesis of DNA, RNA, and proteins required by immune cells. MMF further enhances the aforementioned anti-inflammatory effects by consuming tetrahydrobiopterin, leading to a decrease in inducible nitric oxide synthase activity and consequently reducing the production of peroxynitrite, a pro-inflammatory molecule. Mycophenolic acid (MPA), the active metabolite of mycophenolic esters, is a potent, selective, non-competitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibiting the de novo synthesis of guanosine nucleotides without incorporating itself into DNA. Since the proliferation of T cells and B cells is highly dependent on de novo purine synthesis, while other cell types can utilize salvage pathways, MPA exhibits potent cytoseptic activity against lymphocytes. MPA inhibits the proliferative response of T cells and B cells to mitogens and allogeneic stimuli. The addition of guanosine or deoxyguanosine reverses the cytoseptic effect of MPA on lymphocytes. MPA also inhibits antibody production by B lymphocytes. MPA can prevent the glycosylation of lymphocyte and monocyte glycoproteins involved in lymphocyte-endothelial cell adhesion and may inhibit the recruitment of leukocytes to sites of inflammation and transplant rejection. Mycophenolate mofetil does not inhibit early events of human peripheral blood monocyte activation, such as the production of interleukin-1 and interleukin-2, but it blocks the coupling of these events with DNA synthesis and proliferation. Mycophenolate mofetil (morpholinoethyl mycophenolate) inhibits de novo purine synthesis by inhibiting inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effect involves T cells and B cells, thereby preventing antibody production. Mycophenolate mofetil has immunosuppressive effects when used alone, but is most often used in combination with other immunosuppressants. Mycophenolate mofetil in combination with cyclosporine and glucocorticoids has been studied in a large randomized clinical trial involving nearly 1,500 kidney transplant recipients. These trials demonstrate that mycophenolate mofetil is significantly more effective than placebo or azathioprine in reducing treatment failure rates and the incidence of acute rejection. Furthermore, mycophenolate mofetil may help reduce the incidence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse reaction is gastrointestinal intolerance; hematological abnormalities have also been observed. The reversible cytosolic effect of mycophenolate mofetil allows for dose adjustment or discontinuation, thus avoiding serious toxicity or excessive suppression of the immune system. The occurrence of cytomegalovirus tissue-invasive disease and malignancy is an issue that needs to be evaluated through long-term follow-up studies. Mycophenolate mofetil does not cause the side effects common to other commercially available immunosuppressants, such as nephrotoxicity, hepatotoxicity, hypertension, neurological disorders, electrolyte disturbances, skin diseases, hyperglycemia, hyperuricemia, hypercholesterolemia, dyslipidemia, and bone loss. Preliminary information suggests that mycophenolate mofetil has a favorable benefit-risk ratio for the prevention of rejection in deceased kidney transplants. Data from studies on other types of organ transplantation are encouraging, but limited in number and insufficient to draw definitive conclusions. Long-term follow-up studies are needed to confirm these observations. Despite the high price of mycophenolate mofetil, its benefits in reducing rejection, treatment failure, and associated costs suggest that it is likely cost-effective. [1] Mycophenolic acid is a compound derived from Penicillium lysate and its close relatives. It blocks the de novo synthesis of purine nucleotides by inhibiting inosine monophosphate dehydrogenase (IMP dehydrogenase). Mycophenolic acid has a selective effect on the immune system, inhibiting the proliferation of T cells and lymphocytes as well as the production of antibodies by B cells. It may also inhibit the recruitment of leukocytes to sites of inflammation. See also: Mycophenolic acid (with the active moiety); Mycophenolic esters (its salt form). In summary, our results indicate that mycophenolate mofetil (MMF) inhibits the secretion of TNF-α, IL-1β and NO by microglia; inhibits the secretion of TNF-α by astrocytes; inhibits the proliferation of microglia and astrocytes; has no direct neuroprotective effect on cultured, excitotoxically damaged hippocampal neurons; and exerts its effect by inhibiting glial IMPDH. Given the encouraging animal experiments and open-label clinical trial results of MMF in a variety of central nervous system diseases, MMF appears to be a promising candidate for further research into the treatment of acute brain and spinal cord diseases. [4] Both MMF and DCZ target T lymphocytes and inhibit inflammatory activity, thereby preventing the development of early skin fibrosis in a bleomycin (BLM)-induced mouse scleroderma model. However, MMF is more effective than DCZ in inhibiting fibroblast activation and has a more significant anti-fibrotic effect. These results support the hypothesis that T lymphocytes play an important role in the pathogenesis of scleroderma, and that suppressing T lymphocytes in the early stages of the disease may be an effective strategy for treating human scleroderma. However, targeting T lymphocytes alone may not be a sufficient approach to treating scleroderma. [5]

C23H31NO7

433.4947

433.21

C, 63.73; H, 7.21; N, 3.23; O, 25.83

128794-94-5

Mycophenolate Mofetil-d4;1132748-21-0;Mycophenolate mofetil hydrochloride;116680-01-4

5281078

White to off-white solid powder

1.2±0.1 g/cm3

637.6±55.0 °C at 760 mmHg

95-96ºC

339.4±31.5 °C

0.0±2.0 mmHg at 25°C

1.557

3.15

1

8

10

31

646

0

O1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])OC(C([H])([H])C([H])([H])/C(/C([H])([H])[H])=C(\[H])/C([H])([H])C2C(=C3C(=O)OC([H])([H])C3=C(C([H])([H])[H])C=2OC([H])([H])[H])O[H])=O)C([H])([H])C1([H])[H]

RTGDFNSFWBGLEC-SYZQJQIISA-N

InChI=1S/C23H31NO7/c1-15(5-7-19(25)30-13-10-24-8-11-29-12-9-24)4-6-17-21(26)20-18(14-31-23(20)27)16(2)22(17)28-3/h4,26H,5-14H2,1-3H3/b15-4+

2-morpholin-4-ylethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate

RS61443; Mycophenolic acid; mycophenolate mofetil; 128794-94-5; 115007-34-6; Myfenax; myclausen; Mycophenylate mofetil; Mycophenolic acid morpholinoethyl ester; Mycophenolate mofetil Teva; Mycophenolate mofetil, Cellcept, Myfortic, RS-61443;Mycophenolate mofetil (free acid);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% methylcellulose:20 mg/mL

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Solubility in Formulation 5: 33.33 mg/mL (76.89 mM) in Cremophor EL (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)