How is mycophenolate mofetil (Cellcept) metabolized in patients with a history of organ transplantation and what factors affect its metabolism?

Metabolism of Mycophenolate Mofetil

Mycophenolate mofetil undergoes rapid and complete presystemic metabolism to mycophenolic acid (MPA), the active metabolite, which is then primarily metabolized by hepatic glucuronyl transferase to form the inactive phenolic glucuronide (MPAG), with subsequent enterohepatic recirculation contributing significantly to plasma MPA concentrations. 1

Primary Metabolic Pathway

Mycophenolate mofetil is rapidly hydrolyzed to MPA upon reaching the systemic circulation, with the parent drug becoming undetectable (below 0.4 mcg/mL) within approximately 5 minutes after intravenous infusion stops or after oral administration. 1 This conversion occurs presystemically after oral dosing, meaning the prodrug is metabolized before entering the general circulation. 1

MPA is then metabolized principally by glucuronyl transferase enzymes in the liver to form MPAG, which lacks pharmacologic activity. 1 The EASL guidelines confirm that mycophenolic acid is the active metabolite of MMF and functions as a selective, non-competitive inhibitor of IMPDH. 2

Enterohepatic Recirculation

MPAG undergoes significant enterohepatic recirculation, being converted back to active MPA in vivo, which explains the secondary peaks in plasma MPA concentration typically observed 6 to 12 hours post-dose. 1 This recirculation is clinically significant—cholestyramine (4 g three times daily) decreases MPA AUC by approximately 40% by interrupting this cycle. 1

Excretion and Minor Metabolites

Most of the administered dose (approximately 87%) is excreted in the urine as MPAG, with negligible amounts (<1%) excreted as unchanged MPA. 1 Following oral administration, 93% of the dose is recovered in urine and 6% in feces. 1

Minor metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in urine, including N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. 1

Factors Affecting Metabolism

Gender Differences

Men demonstrate significantly higher glucuronidation rates than women, with MPAG/MPA ratios of 15.0 ± 2.2 in men versus 7.7 ± 0.9 in women. 3 This gender difference must be considered when dosing MMF, as higher glucuronidation in men may favor more rapid MPA elimination.

Concomitant Immunosuppression

Tacrolimus inhibits the glucuronidation of MPA, resulting in lower MPAG/MPA ratios compared to cyclosporine co-treatment. 3 Patients receiving MMF with tacrolimus show reduced conversion to the inactive metabolite compared to those on cyclosporine-based regimens.

Renal Impairment

In patients with renal insufficiency, MPAG accumulates to approximately 3- to 6-fold higher concentrations (and MPA increases by 50%), because MPAG is primarily renally excreted. 1, 4 This accumulation has important consequences:

• MPAG competes with MPA for albumin binding sites, reducing MPA protein binding and increasing free (pharmacologically active) MPA concentrations. 5
• The uremic state itself also decreases MPA protein binding independent of MPAG accumulation. 5
• At MPAG concentrations ≥460 mcg/mL (seen in renal impairment), the free fraction of MPA increases significantly. 1

Organ-Specific Differences

Significant transplanted organ-specific differences exist in MMF pharmacology, with small bowel transplant patients displaying the lowest MPA levels (0.39 ± 0.08 mcg/mL) despite higher mg/kg dosing, compared to liver transplant patients (1.10 ± 0.17 mcg/mL) or renal transplant patients (2.46 ± 0.37 mcg/mL). 6 This suggests separate dose optimization may be needed for each transplant type.

Timing Post-Transplant

In the early post-transplant period (<40 days), renal, cardiac, and hepatic transplant patients have mean MPA AUCs approximately 20-41% lower and mean Cmax approximately 32-44% lower compared to the late transplant period (3-6 months post-transplant). 1

Protein Binding Considerations

MPA is 97% bound to plasma albumin at clinically relevant concentrations, and only the free fraction is pharmacologically active. 1 MPAG is 82% bound to albumin at normal concentrations. 1

Salicylate (at 25 mg/dL) and MPAG (at ≥460 mcg/mL) increase the free fraction of MPA by competing for albumin binding sites. 1 This is particularly relevant in renal impairment where MPAG accumulates.

Renal Transporter Interactions

MPA and its metabolites potently inhibit human organic anion transporters OAT1 (IC50 1.24 μM) and OAT3 (IC50 0.52 μM) in the basolateral membrane of renal tubules. 7 MPAG and AcMPAG also inhibit OAT3 (IC50 15.2 μM and 2.88 μM, respectively). 7 This interaction may interfere with renal secretion of antiviral drugs, cortisol, and other organic anions.

Clinical Implications for Monitoring

Despite fixed dosing regimens (typically 2 g/day), there is enormous interindividual variability in MPA AUC (range 10.1-99.8 mcg/mL·h) and trough levels (range 0.24-7.04 mcg/mL). 8 Patients with AUC >40 mcg/mL·h demonstrate better renal function (creatinine clearance 85.7 ± 23.2 versus 64.5 ± 17.5 mL/min). 8

The percentage of free plasma MPA (not total MPA) correlates with red blood cell and leukocyte counts, suggesting therapeutic drug monitoring of free MPA may help optimize dosing and limit toxicity. 8