Chemical formula: C₂₃H₃₁NO₇ Molecular mass: 433.495 g/mol PubChem compound: 5281078
Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.
Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate mofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.
Following intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to the active metabolite, MPA. The parent substance mycophenolate mofetil can be measured systemically during intravenous infusion. MPA at clinically relevant concentrations is 97% bound to plasma albumin.
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6-12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation. MPA at clinically relevant concentrations is 97% bound to plasma albumin.
MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF’s side effects (diarrhoea, leucopenia).
A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Oral administration of radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (>100μg/mL), small amounts of MPAG are removed. By interfering with enterohepatic recirculation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC.
MPA’s disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.
In the early post-transplant period (<40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3-6 months post-transplant).
In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m²) were 28-75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean single dose MPAG AUC was 3-6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
In patients with delayed renal graft function post-transplant, mean MPA AUC0-12h was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC0-12h was 2-3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of mycophenolate mofetil does not appear to be necessary.
In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) given 600 mg/m² mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving mycophenolate mofetil at a dose of 1 g bid in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.
The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in the elderly patients (≥65 years) when compared to younger transplant patients.
A study of the co-administration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of mycophenolate mofetil on the ovulation suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected. The pharmacokinetics of oral contraceptives were unaffected by co-administration of mycophenolate mofetil.
In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2-3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3-2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.
Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.
Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2-3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3-2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.
The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
