Mycophenolic acid
Encyclopedia
Mycophenolic acid INN
(icon) or mycophenolate is an immunosuppressant
drug used to prevent rejection
in organ transplant
ation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug
mycophenolate mofetil
(MMF) to improve oral bioavailability
. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche
) and Myfortic (mycophenolate sodium; Novartis
).
rejection
. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant
rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver
, heart
, and/or lung transplant
s in children older than two years.
An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in immune-mediated disorders including immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis
.
Its increasing application in treating lupus nephritis
has demonstrated more frequent complete response and less frequent complications compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy. Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide
, again in terms of response and side-effects. Walsh et al. even propose that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in patients without renal dysfunction, suggesting that mycophenolate will be encountered more frequently in medical practice.
(ITP), systemic lupus erythematosus
(SLE), scleroderma
(systemic sclerosis or SSc) and pemphigus
vulgaris (PV) with success for some patients.
It is also currently being used as a long-term therapy for maintaining remission of C-ANCA positive (Wegener's) granulomatosis. A combination of mycophenolate and ribavirin
has been found to stop infection by and replication
of dengue virus in vitro
.
s (≥1% of patients) associated with mycophenolate therapy include diarrhoea, nausea, vomiting, infections, leukopenia
, and/or anemia
. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis
and thrombosis
. Infrequent adverse effects (0.1–1% of patients) include esophagitis
, gastritis
, gastrointestinal tract
hemorrhage, and/or invasive cytomegalovirus
(CMV) infection. Several cases of pure red cell aplasia (PRCA) have also been reported.
The U.S. Food and Drug Administration (FDA) has issued an alert that patients on mycophenolate mofetil and mycophenolic acid are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus
, and BK virus
associated nephropathy. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. The neurological condition known as progressive multifocal leukoencephalopathy
attacks the brain and central nervous system and is usually fatal.
Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.
.. Mycophenolate mofetil is metabolised in the liver
to the active moiety mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the enzyme
that controls the rate of synthesis of guanine monophosphate in the de novo
pathway of purine
synthesis used in the proliferation of B and T lymphocytes.
Mycophenolate is potent and can be used in place of the older anti-proliferative azathioprine
. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin
inhibitor (ciclosporin
or tacrolimus
) and prednisolone
.
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
(icon) or mycophenolate is an immunosuppressant
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
drug used to prevent rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
in organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
ation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
mycophenolate mofetil
Mycophenolate mofetil
Mycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
(MMF) to improve oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
) and Myfortic (mycophenolate sodium; Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
).
Indications
In general, mycophenolate is used for the prevention of organ transplantOrgan transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant
Kidney transplantation
Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ...
rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
, heart
Heart transplantation
A heart transplant, or a cardiac transplantation, is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease. As of 2007 the most common procedure was to take a working heart from a recently deceased organ donor and implant it into the...
, and/or lung transplant
Lung transplantation
Lung transplantation, or pulmonary transplantation is a surgical procedure in which a patient's diseased lungs are partially or totally replaced by lungs which come from a donor...
s in children older than two years.
An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in immune-mediated disorders including immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
.
Its increasing application in treating lupus nephritis
Lupus nephritis
Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus , a disease of the immune system. Apart from the kidneys, SLE can also damage the skin, joints, nervous system and virtually any organ or system in the body....
has demonstrated more frequent complete response and less frequent complications compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy. Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, again in terms of response and side-effects. Walsh et al. even propose that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in patients without renal dysfunction, suggesting that mycophenolate will be encountered more frequently in medical practice.
Comparison to other agents
Compared with azathioprine it has significantly higher incidence of diarrhoea, and no difference in risk of any of the other side effects. Mycophenolic acid is 15 times more expensive than azathioprine The exact role of mycophenolate vs azathioprine has yet to be conclusively established. In long-term immunosuppression, it may be used to avoid calcineurin inhibitors or steroids.Potential future uses
Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpuraIdiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura is the condition of having an abnormally low platelet count of no known cause . As most incidents of ITP appear to be related to the production of antibodies against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to...
(ITP), systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE), scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
(systemic sclerosis or SSc) and pemphigus
Pemphigus
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes.In pemphigus, autoantibodies form against desmoglein. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes...
vulgaris (PV) with success for some patients.
It is also currently being used as a long-term therapy for maintaining remission of C-ANCA positive (Wegener's) granulomatosis. A combination of mycophenolate and ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
has been found to stop infection by and replication
Viral replication
Viral replication is the term used by virologists to describe the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. From the perspective of the virus, the purpose of viral replication is...
of dengue virus in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
.
Adverse effects
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with mycophenolate therapy include diarrhoea, nausea, vomiting, infections, leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, and/or anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
and thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. Infrequent adverse effects (0.1–1% of patients) include esophagitis
Esophagitis
Esophagitis is inflammation of the esophagus. It may be acute or chronic. The acute esophagitis can be catarrhal or phlegmonous, whereas the chronic esophagitis may be hypertrophic or atrophic.-Infectious:...
, gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
, gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
hemorrhage, and/or invasive cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
(CMV) infection. Several cases of pure red cell aplasia (PRCA) have also been reported.
The U.S. Food and Drug Administration (FDA) has issued an alert that patients on mycophenolate mofetil and mycophenolic acid are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
, and BK virus
BK virus
The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.-History:...
associated nephropathy. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. The neurological condition known as progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
attacks the brain and central nervous system and is usually fatal.
Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.
Pharmacology
Mycophenolate is derived from the fungus Penicillium stoloniferum or in P. echinulatumPenicillium echinulatum
Penicillium echinulatum is a mould species in the genus Penicillium. It is a source of cellulase.5-Hydroxymaltol and mycophenolic acid are substances that can be found in P. echinulatum....
.. Mycophenolate mofetil is metabolised in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
to the active moiety mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that controls the rate of synthesis of guanine monophosphate in the de novo
De novo synthesis
De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to their being recycled after partial degradation. For example, nucleotides are not needed in the diet as they can be constructed from small precursor molecules such as...
pathway of purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
synthesis used in the proliferation of B and T lymphocytes.
Mycophenolate is potent and can be used in place of the older anti-proliferative azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
inhibitor (ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
or tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
) and prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
.
External links
- MedlinePlus drug information: mycophenolate (systemic) – information from USP DI Advice for the Patient