Mycophenolate mofetil

Absorption

Mycophenolate mofetil is rapidly absorbed in the small intestine. The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose. The average bioavailability of orally administered mycophenolate mofetil in a pharmacokinetic study of 12 healthy patients was 94%. In healthy volunteers, the Cmax of mycophenolate mofetil was 24.5 (±9.5)μg/mL. In renal transplant patients 5 days post-transplant, Cmax was 12.0 (±3.82) μg/mL, increasing to 24.1 (±12.1)μg/mL 3 months after transplantation. AUC values were 63.9 (±16.2) μg?h/mL in healthy volunteers after one dose, and 40.8 (±11.4) μg?h/mL, and 65.3 (±35.4)μg?h/mL 5 days and 3 months after a renal transplant, respectively. The absorption of mycophenolate mofetil is not affected by food.

Toxicity

LD50
The LD50 of oral mycophenolate mofetil in rats is 250 mg/kg and >4000 mg/kg in mice.
Overdose information
Possible signs and symptoms of acute overdose may consist of hematological abnormalities including leukopenia and neutropenia, and gastrointestinal symptoms.

Description

Mycophenolate mofetil was launched in 1995 in the U.S.A., its first market worldwide, for the prevention of acute kidney transplant rejection in conjunction with other immunosuppressive therapy and to treat refractory acute kidney graft rejection. With improved oral absorption and bioavailability, mycophenolate mofetil is a prodrug of mycophenolic acid (MPA), a fermentation product of several Penicillium species. MPA is a selective, reversible, non-competitive inhibitor of inosinate dehydrogenase and guanylate synthetase. It inhibits the de now pathway of purine biosynthesis. MPA was found to have more potent antiproliferative effects on T and B lymphocytes than other cell types. Compared with other immunosuppressants, mycophenolate mofetil is reportedly superior due to its unique mechanism of action and excellent safety profile for long term use. Mycophenolate mofetil is being investigated clinically in the treatment of heart and liver transplantation rejection, asthma, in preventing coronary artery restenosis, and in treating rheumatoid arthritis.

Chemical properties

White Powder

Originator

Roche (Switzerland)

The Uses of Mycophenolate mofetil

For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.

The Uses of Mycophenolate mofetil

An immunosuppressant.

The Uses of Mycophenolate mofetil

Mycophenolate mofetil has been used to treat wild-type embryos for inhibiting nucleotide synthesis.

Indications

Mycophenolate mofetil is indicated in combination with other immunosuppressants to prevent the rejection of kidney, heart, or liver transplants in adult and pediatric patients ≥3 months old. Mycophenolate mofetil may also be used off-label as a second-line treatment for autoimmune hepatitis that has not responded adequately to first-line therapy. Other off-label uses of this drug include lupus-associated nephritis and dermatitis in children.

Background

Mycophenolate mofetil, also known as MMF or CellCept, is a prodrug of mycophenolic acid, and classified as a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). This drug is an immunosuppressant combined with drugs such as Cyclosporine and corticosteroids to prevent organ rejection after hepatic, renal, and cardiac transplants. It is marketed by Roche Pharmaceuticals and was granted FDA approval for the prophylaxis of transplant rejection in 1995. In addition to the above uses, mycophenolate mofetil has also been studied for the treatment of nephritis and other complications of autoimmune diseases. Unlike another immunosuppressant class, the calcineurin inhibitors, MMF generally does not cause nephrotoxicity or fibrosis.
Previously, mycophenolic acid (MPA) was administered to individuals with autoimmune diseases beginning in the 1970s, but was discontinued due to gastrointestinal effects and concerns over carcinogenicity. The new semi-synthetic 2-morpholinoethyl ester of MPA was synthesized to avoid the gastrointestinal effects associated with the administration of MPA. It demonstrates an increased bioavailability, a higher efficacy, and reduced gastrointestinal effects when compared to MPA.

What are the applications of Application

Mycophenolate mofetil is a compound that suppresses T-lymphocytic and antibody responses

Definition

ChEBI: A carboxylic ester resulting from the formal condensation between the carboxylic acid group of mycophenolic acid and the hydroxy group of 2-(morpholin-4-yl)ethanol. In the liver, it is metabolised to mycophenolic acid, an immunosuppressant for which it is prodrug. It is widely used to prevent tissue rejection following organ transplants as well as for the treatment of certain autoimmune diseases.

Indications

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-derived immunosuppressive agent that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo the guanosine nucleotides required for DNA and RNA synthesis.MPA has been used for decades as a systemic treatment for moderate to severe psoriasis. MMF was developed to increase the bioavailability of MPA.

Manufacturing Process

The synthesis of Mycophenolic acid (Canonica L. Et al., Tetrahedron Letters, 1971, N 28, p.2691-2692)
By condensation of sodium diethylmalonate and 3-methylpent-3-en-2-on in ethanol was obtained 2,3-dimethyl-4,6-dioxocyclohexanecarboxilic acid ethyl ester, which was aromatised to 4,6-dihydroxy-2,3-dimethylbenzoic acid ethyl ester (melting point 115-116°C). By treatment with diazomethane or with CH3I and K2CO3 this compound was transformed into 2,4-dimethoxy-5,6- dimethylbenzoic acid ethyl ester (melting point 62-63°C). The hydrolysis of the ester group furnished the 2,4-dimethoxy-5,6-dimethylbenzoic acid (melting point 208-210°C), which was converted into the amide: carbamic acid 3-methoxy-4,5,6-trimethylphenyl ester (melting point 225-229°C). Treatment of the amide with t-butylhypochlorite in methylene dichloride yielded the corresponding N-chloroamide which was photolysed to the intermediate iminolactone and was immediately hydrolized to 5,7-dimethoxy- 4-methyl-3H-isobenzofuran-1-one.
This compound with hydriodic acid in acetic acid in the presence of red phosphorous at reflux yielded 5,7-dihydroxy-4-methyl-3H-isobenzofuran-1- one. Condensation of 6-bromo-4-methylhex-4-enoic acid methyl ester and 5,7-dihydroxy-4-methyl-3H-isobenzofuran-1-one with silver oxide in dioxane at room temperature yielded 6-(4,6-dihydroxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid methyl ester (36% yield). At last, monomethylation with diazomethane yield 6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methylhex-4-enoic acid methyl ester, which was hydrolysed with aqueous sodium hydroxide to 6-(4- hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4- methylhex-4-enoic acid (Mycophenolic acid).
Mycophenolic acid may be obtained by the fermentation broth of Pennicillium brevicompactum. The synthesis of Mycophenolate mofetil (Patent U.S. 4,753,935). The mixture of Mycophenolic acid (32.0 g), thionyl chloride (25.0 ml) and DMF (0.3 ml) in dichloromethane (250 ml) was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford mycophenolic acid chloride as an oil. The mycophenolic acid chloride oil was dissolved in dichloromethane (50.0 ml) and added to the chilled solution of morpholinoethanol (30.5 ml) in dichloromethane (250 ml). After stirring for 90 min at 4°C, the reaction mixture was washed with water and then with aqueous sodium bicarbonate. The organic solution was dried with sodium sulfate and evaporated to yield Mycophenolate mofetil: morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (melting point 93-94°C).
The product (38.0 g) was dissolved in isopropanol (200 ml) and the solution was added to a solution of hydrogen chloride (10.0 g) in isopropanol (150 ml). The hydrochloride of Mycophenolate mofetil was collected by filtration and dried under vacuum (melting point 154-155°C).

brand name

CellCept

Therapeutic Function

Antiarthritic, Immunosuppressive

Biochem/physiol Actions

Mycophenolate mofetil is a prodrug of mycophenolic acid (Cat. # M5255) that is cleaved by nonspecific esterases in vivo to produce the parent compound. Mycophenolic acid blocks inosine monophosphate dehydrogenase and is a potent immunosuppresive agent.

Mechanism of action

the guanosine nucleotides required for DNA and RNA synthesis.MPA has been used for decades as a systemic treatment for moderate to severe psoriasis. MMF was developed to increase the bioavailability of MPA.

Pharmacokinetics

Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA). The active form of mycophenolate, MPA, prevents the proliferation of immune cells and the formation of antibodies that cause transplant rejection. The above effects lead to higher rates of successful transplantation, avoiding the devastating effects of graft rejection.

Clinical Use

MMF is indicated for the prophylaxis of organ rejection in patients receiving renal, hepatic, and cardiac transplants; it is often used in combination with other immunosuppressive agents for this indication. In dermatology, MMF is particularly useful as monotherapy, or as a steroid-sparing agent, for treatment of autoimmune blistering diseases (bullous pemphigoid and pemphigus). It may also be useful for the treatment of inflammatory skin diseases mediated by neutrophilic infiltration, such as pyoderma gangrenosum, and psoriasis.

Side Effects

Adverse effects produced by MMF most commonly include nausea, abdominal cramps, diarrhea, and possibly an increased incidence of viral and bacterial infections. Whether MMF may be associated with an increased long-term risk of lymphoma or other malignancies is controversial; however, any such risk is likely to be lower in patients treated for skin disease with MMF monotherapy than in transplant patients treated with combination immunosuppressive therapy.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: higher concentrations of both mycophenolate and aciclovir or ganciclovir when the two are prescribed concomitantly
. Antacids: absorption of mycophenolate decreased in presence of magnesium and aluminium salts. Antibacterials: bioavailability of mycophenolate possibly reduced by metronidazole and norfloxacin; concentration of active metabolite reduced by rifampicin.
Colestyramine: 40% reduction in oral bioavailability of mycophenolate.
Ciclosporin: some studies show that ciclosporin decreases plasma MPA AUC levels; other studies show increases - no dose change required.
Iron preparations: may significantly reduce absorption of mycophenolate.
Sevelamer: reduced levels of mycophenolate.
Tacrolimus: increases MPA concentrations- no dose change required but monitor closely.
See 'Other information'

Metabolism

After both oral and intravenous administration mycophenolate mofetil is entirely metabolized by liver carboxylesterases 1 and 2 to mycophenolic acid (MPA), the active parent drug. It is then metabolized by the enzyme glucuronyl transferase, producing the inactive phenolic glucuronide of MPA (MPAG). The glucuronide metabolite is important, as it is then converted to MPA through enterohepatic recirculation. Mycophenolate mofetil that escapes metabolism in the intestine enters the liver via the portal vein and is transformed to pharmacologically active MPA in the liver cells.N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide portion of N-(2-hydroxyethyl)-morpholine are additional metabolites of MMF occurring in the intestine as a result of liver carboxylesterase 2 activity. UGT1A9 and UGT2B7 in the liver are the major enzymes contributing to the metabolism of MPA in addition to other UGT enzymes, which also play a role in MPA metabolism. The four major metabolites of MPA are 7-O-MPA-β-glucuronide (MPAG, inactive), MPA acyl-glucuronide (AcMPAG), produced by uridine 5?-diphosphate glucuronosyltransferases (UGT) activities, 7-O-MPA glucoside produced via UGT, and small amounts 6-O-des-methyl-MPA (DM-MPA) via CYP3A4/5 and CYP2C8 enzymes.

Metabolism

Mycophenolate undergoes presystemic metabolism in the liver to active mycophenolic acid (MPA). MPA undergoes enterohepatic recirculation and secondary increases in plasma MPA concentrations are seen; these have been reported at between 6-12 hours after a dose of mycophenolate mofetil, and at between 6-8 hours after a dose of mycophenolate sodium. MPA is metabolised by glucuronidation to the inactive mycophenolic acid glucuronide. The majority of a dose of mycophenolate is excreted in the urine as this glucuronide, with negligible amounts of MPA; about 6% of a dose is recovered in faeces.

storage

Store at RT

References

1) Allison and Eugui (1996), Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF); Clin. Transplant., 10 77 2) Jonsson et al. (2002), Mycophenolic acid inhibits inosine 5′-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages; Cell. Immunol., 216 93 3) Allison et al. (1993), Mechanisms of action of mycophenolic acid; Ann. NY Acad. Sci., 696 63 4) Quemeneur et al. (2002), Mycophenolic acid inhibits IL-2-dependent T cell proliferation, but not IL-2-dependent survival and sensitization to apoptosis; J. Immunol., 169 2747 5) Ebrahimi et al. (2012) Time dependent neuroprotection of mycophenolate mofetil; effects on temporal dynamics in glial proliferation, apoptosis, and scar formation; J. Neuroinflammation, 9 89