Drug Groups

approved; investigational

Description

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent, inosine monophosphate dehydrogenase (IMPDH) inhibitor.

Indication

For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.

Pharmacology

Mycophenolate mofetil is a prodrug of mycophenolic acid, an antibiotic substance derived from Penicillium stoloniferum. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase. Mycophenolic acid is important because of its selective effects on the immune system. It prevents the proliferation of T-cells, lymphocytes, and the formation of antibodies from B-cells. It also may inhibit recruitment of leukocytes to inflammatory sites.

Toxicity

Oral (LD50): Acute: 352 mg/kg [Rat], 1000 mg/kg [Mouse], and >6000 mg/kg [Rabbit]. Possible signs and symptoms of acute overdose could include the following: hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia.

Affected Organisms

Biotransformation

Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Absorption

Rapidly absorbed following oral administration. In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. Food (27 g fat, 650 calories) has no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil.

Half Life

The mean elimination half-life for mycophenolic acid (the active metabolite) ranges from 8-16 hours, while that of the MPAG metabolite ranges from 13-17 hours.

Protein Binding

MPA (the active metabolite), at clinically relevant concentrations, is over 98% bound to plasma albumin.

Elimination

Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Most (about 87%) of the administered dose is excreted in the urine as MPAG.

Distribution

* 3.6 ±1.5 L/kg [intravenous]
* 4 ±1.2 L/kg [oral administration]

Clearance

* 193 +/- 48 mL/min [following oral administration]

References

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