What is mycophenolic acid?

Mycophenolic Acid: An Immunosuppressive Agent

Mycophenolic acid (MPA) is a potent, selective, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) that blocks the de novo synthesis of guanosine nucleotides, thereby inhibiting T and B lymphocyte proliferation. It is primarily used as an immunosuppressant to prevent organ rejection in transplant patients and to treat certain autoimmune conditions.

Mechanism of Action

• MPA works by inhibiting IMPDH, an enzyme critical for the de novo pathway of guanosine nucleotide synthesis 1, 2
• This inhibition preferentially affects T and B lymphocytes, which are critically dependent on this pathway for proliferation 1, 2
• MPA causes decreased B and T cell proliferation, T cell apoptosis, and suppression of dendritic cells and IL-1 1

Formulations

• Available as mycophenolate mofetil (MMF), a prodrug that is completely metabolized to MPA after oral administration 1, 3
• Also available as enteric-coated mycophenolate sodium (EC-MPS), developed to reduce gastrointestinal side effects 1, 4
• These formulations should not be used interchangeably due to different pharmacokinetic profiles 2

Clinical Applications

FDA-Approved Indications

• Prophylaxis of organ rejection in adult kidney transplant recipients 2
• Prophylaxis of organ rejection in pediatric kidney transplant patients at least 5 years of age and older who are at least 6 months post-transplant 2
• Must be used in combination with cyclosporine and corticosteroids 2

Off-Label Uses

• Liver transplantation: Used as an antimetabolite to reduce CNI doses and minimize nephrotoxicity 1
• Treatment of autoimmune disorders including lupus, myasthenia gravis, and glomerular disorders 3
• Management of psoriasis: Originally used in the 1970s but associated with high incidence of gastrointestinal and infectious adverse effects 1
• Treatment of steroid-refractory acute graft-versus-host disease (aGVHD) 1
• Management of immune thrombocytopenia 1
• Treatment of steroid-refractory immune-related adverse events from cancer immunotherapy 1

Pharmacokinetics

• Absorption: EC-MPS exhibits a median lag time in absorption of 0.25-1.25 hours compared to MMF 1, 5
• Distribution: MPA is highly protein-bound (>98% to albumin) 2, 5
• Metabolism: Primarily metabolized to mycophenolic acid glucuronide (MPAG), which is pharmacologically inactive 2, 5
• Elimination: Mean elimination half-life ranges from 8-16 hours for MPA 2, 5
• Enterohepatic recirculation: MPAG is excreted into bile, deconjugated by gut bacteria back to MPA, and reabsorbed in the colon, contributing approximately 40% to the AUC 5

Adverse Effects

• Gastrointestinal: Diarrhea, nausea, vomiting, abdominal cramps (up to 35% of patients) 1, 4
• Hematologic: Leukopenia, anemia, thrombocytopenia 1, 2
• Genitourinary: Urgency, frequency, dysuria 1
• Increased susceptibility to infections, including opportunistic infections 2
• Risk of malignancies, particularly of the skin, due to immunosuppression 2
• Embryo-fetal toxicity: Associated with increased risks of pregnancy loss and congenital malformations 2

Drug Interactions

• Antacids with magnesium and aluminum hydroxides: Decrease MPA concentrations 2
• Azathioprine: Competition for purine metabolism; concomitant use not recommended 2
• Cholestyramine and other drugs that interfere with enterohepatic recirculation: May decrease MPA concentrations 2
• Cyclosporine: Inhibits biliary excretion of MPAG, reducing enterohepatic recirculation of MPA 5
• Rifampin: May decrease MPA concentrations 2
• Hormonal contraceptives: May reduce effectiveness of oral contraceptives 2

Monitoring

• Therapeutic drug monitoring may be beneficial due to wide inter-individual pharmacokinetic variability 6, 5
• Target MPA AUC from 0 to 12 hours of 30-60 mg·hr/L to minimize rejection risk and reduce toxicity 5
• Regular monitoring of complete blood counts to detect myelosuppression 2
• Monitor for signs of infection and malignancy 2

Special Populations

• Renal impairment: MPA plasma protein binding may be altered, changing free MPA fraction 5
• Hepatic impairment: May affect MPA metabolism and clearance 5
• Pregnancy: Avoid if safer treatment options are available; associated with increased risk of pregnancy loss and congenital malformations 2
• Elderly: Dose selection should be cautious due to greater frequency of decreased organ function 2

Mycophenolic acid represents an important immunosuppressive agent in transplantation medicine and increasingly in autoimmune disorders, with its selective inhibition of lymphocyte proliferation providing effective immunosuppression while potentially avoiding some of the toxicities associated with other immunosuppressive regimens.