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)
Uses
An immunosuppressant.
Uses
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.
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).
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.
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
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.
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
