Factors That Can Elevate Mycophenolic Acid (MPA) Levels
Several medications and clinical factors can elevate mycophenolic acid levels even in patients who don't take mycophenolate mofetil, including renal impairment, drug interactions (particularly antibiotics that disrupt gut flora), and decreased protein binding.
Drug Interactions That Increase MPA Levels
Medications That Disrupt Enterohepatic Recirculation
- Antibiotics: Certain antibiotics can significantly increase MPA levels by disrupting gut flora involved in enterohepatic recirculation 1
- Ciprofloxacin can increase MPA levels by approximately 50%
- Amoxicillin plus clavulanic acid can increase MPA levels by approximately 50%
Medications That Affect Renal Clearance
- Probenecid: Inhibits tubular secretion and can increase MPA levels by approximately 2-fold 1
- Other drugs that undergo renal tubular secretion: May compete with MPAG (MPA glucuronide) and raise MPA concentrations 1
- Tacrolimus: Can increase MPA levels compared to cyclosporine 2
Patient Factors That Increase MPA Levels
Physiological Factors
- Renal impairment: Decreases clearance of MPA and its metabolites, leading to 50% increase in MPA and 3-6 fold increase in MPAG 1
- Hypoalbuminemia: Decreases protein binding, increasing free MPA fraction and toxicity 3
- Liver dysfunction: Impairs metabolism of MPA, particularly with hyperbilirubinemia 3
Formulation Differences
- Enteric-coated mycophenolate sodium (EC-MPS): Can result in higher MPA trough levels compared to equivalent doses of mycophenolate mofetil in patients with GI intolerance 4
- In one study, MPA levels increased from 1.5 μg/mL to 2.5 μg/mL after switching to EC-MPS despite equipotent dosing 4
Monitoring and Management
Signs of MPA Toxicity
- Hematologic effects: Leukopenia, anemia, thrombocytopenia
- Gastrointestinal effects: Severe diarrhea, nausea, vomiting, abdominal pain
- Infectious complications: Opportunistic infections
- Metabolic disturbances: Hypophosphatemia, hypokalemia, hyperglycemia 2
Management Approach
- Identify potential causes of elevated MPA levels
- Consider temporary dose reduction of any mycophenolate product if present
- Monitor CBC weekly after any intervention until stabilization 2
- Consider switching formulations from MMF to EC-MPS if GI side effects are present 2
Clinical Pearls and Pitfalls
- Pitfall: Assuming normal MPA levels in patients with renal dysfunction who aren't taking mycophenolate
- Pitfall: Overlooking antibiotic interactions that can significantly raise MPA levels
- Pearl: In patients with hypoalbuminemia, free MPA levels may be elevated even when total MPA levels appear normal 3
- Pearl: Asian patients may have higher MPA levels at equivalent doses compared to non-Asians 2
Special Considerations
The American College of Rheumatology notes that mycophenolate-containing medications may interfere with hormonal contraceptive efficacy, suggesting a bidirectional interaction potential between these drug classes 5.
For patients with rheumatic diseases who require mycophenolate therapy and contraception, IUDs alone or two other methods of contraception together are recommended due to potential interactions 5.
Human organic anion transporters (OAT1 and OAT3) are significantly inhibited by MPA, which may explain some drug interactions and altered clearance patterns 6.