Mycophenolic acid, metabolism

Goosen TC, Arimoto R, Gifford E, Ball SE, Hurst SI, Tugnait M, Hollenberg PF, Williams JA. A computational model based on UGTIA inhibition in human liver microsomes predicts the tacrolimus-mycophenolic acid metabolic drug interaction. Drug Metab Rev 2003 35 58. 

The active metabolite of this drug is mycophenolic acid (MPA), which inhibits IMPDH, too. MPA is metabolized in vivo by glucuronidation. It has to be noted that its acyl glucuronide inhibits EVDPDH with similar potency compared to the parent compound. 

Metabolism/Excretion - Negligible amount of drug is excreted as mycophenolic acid (less than 1% of dose) in the urine. Oral administration resulted in complete recovery of the administered dose 93% was recovered in the urine and 6% recovered in feces. Mean apparent half-life of mycophenolic acid is about 17.9 hours following oral administration. 

Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 system is not involved, some drug interactions still occur. Plasma drug levels are frequently monitored, similar to the calcineurin inhibitors and PSIs. 

The metabolism of mycophenolate is altered by coadministration with cyclosporine. Mycophenolic acid (MPA) levels are lower when mycophenolate mofetil is compared with cyclosporine. Lower doses should be considered in recipients receiving tacrolimus or steroids done without a calcineurin inhibitor. 

Mycophenolic acid (Figure 3.36) is produced by fermentation cultures of the fungus Penicillium brevicompactum. It has been known for many years to have antibacterial, antifungal, antiviral, and antitumour properties. It has recently been introduced into medicine as an immunosuppressant drug, to reduce the incidence of rejection of transplanted organs, particularly kidney and heart transplants. It is formulated as the /V-morpholinoethyl ester mycophenolate mofetil (Figure 3.37), which is metabolized after ingestion to mycophenolic... 

Picard N, Ratanasavanh D, Premaud A, et al. Identification of the UDP-glucur-onosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 2005 33(1) 139-146. 

METRONIDAZOLE MYCOPHENOLATE Likely 1 in plasma concentration of mycophenolate Theoretically, drugs that alter gastrointestinal flora may 1 oral bioavailability of mycophenolic acid products by 1 bacterial hydrolytic enzymes that are responsible for regenerating mycophenolic acid from its glu-curonide metabolites following first-pass metabolism Avoid co-administration... 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Bernard, O. and Guillemette, C. (2004) The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effect of naturally occurring variants. Drug Metabolism and Disposition The Biological Fate of Chemicals, 32, 775—778. 

Westley. LS.. Brogan, L.R., Morris. R.G., Evans. A.M.. and Sallustio, B.C. (2006) Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites effect of cyclosporine. Drug Metabolism and Disposition, 34 (2). 261-266. 

Bernard, O., Tojcic, J., Journault, K., Perusse, L., and Guillemette, C. (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab. Dispos. 34 (9), 1539-1545. 

Ciclosporin is known to inhibit the metabolism of mycophenolate, producing lower levels of mycophenolic acid, see Mycophenolate + Ciclosporin or Tacrolimus , p.l067. Whether sirolimus specifically raises mycopheno-lafe levels compared wifh mycophenolafe faken on its own is unclear, however raised mycophenolic acid levels have been associated with an increased risk of adverse effects. " The authors of one of the studies suggest that the mycophenolate dose should be reduced from 1 g to 750 mg twice daily in patients taking sirolimus, as this produced comparable myeophenolie acid levels values with the recommended dose of mycopheno-... 

The authors proposed that mycophenolate mofetil may have enhanced the neurotoxicity of aciclovir, since mycophenolate is thought not to be neurotoxic. Mycophenolic acid is metabolized in the liver to mycophenolic glu-curonide, which may compete with aciclovir for renal tubular secretion. As the combination of mycophenolate mofetil with aciclovir has been reported to have a possible synergistic antiherpes effect, it is important to be aware of a possible increase in the risk of neurotoxicity associated with this combination. 

Mycophenolate mofetil (CdlCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an inactive glucuronide. 

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