**6.9. MMF exposure and metabolism**

nesemia. Proposed mechanisms mediating this effect includes, decreased aldosterone pro‐ duction secondary to cyclosporine, as well as decreased transcription and expression of

Since calcineurin is a ubiquitous enzyme, there are other non-renal toxicities associated with CNI use. Tacrolimus is associated with neurotocity, GI side effects and pancreatic islet toxicity. Neurotoxicity can be as benign as tremors, but in some cases can be quite severe and lead to seizures and altered mental status. Finally, Tacrolimus use has been associated with posterior reversible encephalopathy syndrome (PRES) which can present with various neurological manifestations.[28] Another important clinical issue is the development of new onset posttransplant diabetes, or worsening diabetes post-transplant, particularly with tacrolimus. Neuro and pancreatic toxicity of tacrolimus are clinically handled by either dose reduction or conversion to cyclosporine. Cyclosporine use however can cause gingival hyperplasia, hirsutism, hypercholesterolemia, hypertension, salt retention and an increased incidence of gout. Both CNIs have been linked to increased risk of infectious complications as well as post transplant malignancies. Differences in adverse effects among the CNIs as well as other

The current challenge is to mitigate the side effects of CNIs without sacrificing overall graft outcomes. Several novel protocols are recently designed and studied to overcome CNI toxicity.

Mycophenolate mofetil (MMF) is a maintenance immunosuppressant used often in combina‐ tion with CNIs and steroids. MMF was introduced in 1995 and has largely replaced azathio‐ prine in transplantation, as clinical trials showed superiority of MMF when compared to azathioprine. [29] Based on a recent SRTR report in 2009, MMF was part of the initial mainte‐

Mycophenolate mofetil is an inactive prodrug with mycophenolic acid (MPA) being its active component. The mofetil entity significantly increases bioavailability of MPA. There is an enteric coated form of MPA also available for use that may be better tolerated in some patients. MPA is a selective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which is the rate-limiting enzyme in the denovo synthesis of purines. T- and B-lymphocytes are more dependent on this pathway than other cell types for proliferation since they do not have a salvage pathway for purine synthesis. Moreover, MPA is a more potent inhibitor of the type II isoform of IMPDH, which is predominatly expressed in activated lymphocytes.

MMF was initially approved for standard dose administration of 1 gram twice daily in adult kidney transplant recipients. Therapeutic drug monitoring for MMF/MPA is not performed routinely since several factors can impact the MPA AUC (detailed in the section below). Recent

We have summarized these in the section of new evolving protocols.

nance regimen in 89.9% of kidney transplant recipients.

mineralocorticoid receptor due to prograf.

214 Current Issues and Future Direction in Kidney Transplantation

maintenance agents are shown in Table 3.

**6.6. Mycophenolate mofetil**

**6.7. Mechanism of action**

**6.8. Clinical use**

Mycophenolate moefetil is rapidly absorbed and hydrolysed to yield the active component MPA mainly in the liver, which is detectable in peripheral blood within 1-2 hours. MPA is then converted to 7-0-MPA glucuronide also referred to as MPAG (an inactive metabolite) by UDPglucuronosyl transferase (UDPGT) in the liver and intestine. MPAG is excreted through the bile and urine. Both MPA and MPAG are protein bound. So factors such as low albumin concentra‐ tion and high urea levels can decrease protein binding and lead to rapid clearance of the drug. MPAG accumulation in renal failure displaces MPA from protein binding and can lead to an in‐ crease in the free fraction of the drug. Once MPAG is excreted in the bile it can be converted back to MPA by bacterial glucuronidases and lead to increased levels of MPA (enterohepatic recircu‐ lation). This leads to a second peak in the drug concentration 6 to 12 hours after administration which contributes to more than 30% of the area under the curve. Cyclosporine leads to inhibi‐ tion of this second peak by blocking the transporters involved in biliary excretion of MPAG. So typically patients on cyclosporine need higher doses of MMF or MPA compared to patients on tacrolimus. Antibiotic therapy is also known to have a similar impact by inhibiting bacterial proliferation in the gut and hence inhibiting enterohepatic recirculation.

There is no significant drug interaction with medications that induce or block the CYP3A pathway. When used in combination with sirolimus both agents can lead to cytopenias. Generally co administration with antacids and cholestyramine should be avoided as they interfere with absorption of MMF.
