Microbial Metabolite; Human Endogenous Metabolite

Numerous RNA viruses, such as the hantavirus, rotavirus, CCHFV, dengue virus, influenza, and Zika virus, are susceptible to the antiviral actions of mycophenolic acid [1]. The virus's rate-limiting enzyme is called IMPDH. On endothelial cells and fibroblasts, de novo mycophenolate mofetil (0.01-1 μM; 72 hours) shows selective antiproliferative action. The most susceptible cells to mycophenolic acid therapy are endothelial cells, and the antimitotic action of this compound has an IC50 < synthesis [2]. In comparison to endothelial cells, fibroblasts have a greater IC50 (<1 μM) for mycophenolic acid-induced cell cycle inhibition. A549 non-small cell lung cancer cells, 500 nM, are two human tumor cell lines [2]. and PC3 cadavers had IC50 >1 μM and modest body weight. Up to 1 μM of MPA therapy does not affect U87 astrocytes [2]. Mycophenolic acid on HDAC2 (0.05–2 μM; 18 hours)

Mycophenolic acid regulates the tumor microenvironment to greatly limit the formation of U87 tumors in BALB/c nude mice [2].

cell proliferation assay [2]
Cell Types: primary isolated human dermal microvascular endothelial cells (HDMVEC), fibroblasts, U87 glioblastoma cells, PC3 prostate cancer In cells, A549 non- and MYC exhibit debt invoicing, which is upregulated by NDRG1[2]. Small cell lung cancer cells
Tested Concentrations: 0.01, 0.1, 1 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: demonstrated preferential anti-proliferative activity on HDMVEC and fibroblasts. U87 glioblastoma cells were resistant to treatment, whereas A549 non-small cell lung cancer and PC3 prostate cancer cells demonstrated intermediate sensitivity.

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Western Blot Analysis[2]
Cell Types: HDMVEC
Tested Concentrations: 0, 0.05, 0.1, 0.5, 1 and 2 μM
Incubation Duration: 18 hrs (hours)
Experimental Results: Shows dose-dependent regulation of HDAC2, MYC and NDRG1.

Animal/Disease Models: Athymic 8weeks old, 20 g BALB/c nu/nu mycophenolic acid-bearing mouse drug-resistant human U87 tumor model [2]
Doses: 120 mg/kg MMF (mycophenolate mofetil prodrug) Mode of
Route of Administration: po (oral gavage); bid
Experimental Results: Compared with control mice, MMF (mycophenolate mofetil prodrug) Dramatically inhibited tumor growth in MMF-treated mice (approximately 14 days after tumor implantation) 70%). Microvessel density (CD31 staining) and pericyte coverage measured by α-smooth muscle actin staining were Dramatically diminished in MMF-treated tumors compared with control tumors (44% and 78%, respectively).

Absorption, Distribution and Excretion
Between 360 mg and 2,160 mg, mycophenolic acid follows a linear and dose-proportional pharmacokinetic profile. The enteric-coating of mycophenolic acid tablets prevents release under acidic conditions (stomach, pH < 5). However, enteric-coated mycophenolic acid tablets are highly soluble in neutral pH conditions such as those in the intestine. In renal transplant patients, the median delay (Tlag) in the rise of mycophenolic acid concentration ranged between 0.25 and 1.25 hours, and the Tmax ranged between 1.5 and 2.75 hours. Adult renal transplant patients on cyclosporine given mycophenolic acid had a Tmax of 2 h, a Cmax of 26.1 μg/mL, and an AUC0-12 of 66.5 μg⋅h/mL. Stable pediatric (5-16 years old) renal transplant patients had a Cmax and AUC 33% and 18% higher than the ones detected in adults. In stable renal transplant patients treated with cyclosporine, the gastrointestinal absorption and absolute bioavailability of delayed-release tablets of mycophenolic acid were 93% and 72%, respectively. Following the administration of a high-fat meal (55 g fat, 1000 calories), the AUC of mycophenolic acid (enteric-coated tablets, 720 mg) was comparable to the one detected during fasting. However, a high-fat meal can lead to a 33% decrease of the Cmax, a 3.5-hour delay in the Tlag (range of -6 to 18 hours), and a 5.0-hour delay in the Tmax (range of -9 to 20 hours). To avoid variability in the absorption of mycophenolic acid, this drug should be taken on an empty stomach.
In stable renal transplant patients, approximately 60% of mycophenolic acid is eliminated in the urine as mycophenolic acid glucuronide (MPAG), while 3% is eliminated unchanged. MPAG is also secreted in the bile and is available for deconjugation by gut flora. The mycophenolic acid that results from MPAG deconjugation may be reabsorbed and produce a second peak 6-8 hours after administration.
At steady state, the volume of distribution of mycophenolic acid is 54 L. At the elimination phase, the volume of distribution of mycophenolic acid is 112 L.
The mean clearance of mycophenolic acid is 140 mL/min. The mean renal clearance of its metabolite, mycophenolic acid glucuronide, is 15.5 mL/min.

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Metabolism / Metabolites
Mycophenolic acid is mainly metabolized by glucuronyl transferase to form glucuronidated metabolites. Mycophenolic acid glucuronide (MPAG), the major metabolite of mycophenolic acid, does not display pharmacological activity. However, the acyl glucuronide minor metabolite has a pharmacological activity similar to mycophenolic acid. The AUC ratio of mycophenolic acid:MPAG:acyl glucuronide is approximately 1:24:0.28 at a steady state.
Mycophenolic acid has known human metabolites that include Mycophenolic acid glucuronide and 6-O-desmethyl-MPA (DM-MPA).
Mycophenolic acid is metabolized mainly by glucuronyl transferase to glucuronidated metabolites, predominantly the phenolic glucuronide, mycophenolic acid glucuronide (MPAG). MPAG does not manifest pharmacological activity. The acyl glucuronide minor metabolite has pharmacological activity similar to mycophenolic acid. The AUC ratio of Mycophenolic acid:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state.
Half Life: The mean elimination half-life for mycophenolic acid ranges from 8-16 hours, while that of the MPAG metabolite ranges from 13-17 hours.

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Biological Half-Life
The mean elimination half-life of mycophenolic acid ranges between 8 and 16 hours, while the mean elimination half-life of mycophenolic acid glucuronide, its major metabolite, ranges between 13 and 17 hours.

Hepatotoxicity
Serum enzyme elevations occur in a small proportion of patients on mycophenolate mofetil, but the abnormalities are usually mild, asymptomatic and resolve spontaneously or with dose reduction. A small number of cases of clinically apparent liver injury have been reported in patients on mycophenolate. The onset of injury is usually during the first month of therapy and the pattern of serum enzyme elevations is hepatocellular or mixed. The liver injury is usually mild and self-limiting. Autoimmune and immunoallergic features are uncommon.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Information from 3 patients on the excretion of mycophenolate into milk is inconsistent. A few infants have reportedly been breastfed during mycophenolate therapy, with no adverse effects reported. Because little information is available on the use of mycophenolate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
The National Transplantation Pregnancy Registry (renamed Transplant Pregnancy Registry International) collected information on 6 mothers (5 kidney and 2 heart transplants) who breastfed 7 infants while taking a mycophenolate product. The maximum time that any of the infants was breastfed was 14 months. None of the infants had any reported adverse reactions. Another case series from the Transplant Pregnancy Registry International reported women who received heart transplants reported that 3 women breastfed their infants while taking mycophenolate. Durations of breastfeeding and infant outcomes were not reported. It is possible that some of these women were the same as those in the case series above.
In case series of 77 patients from the UK who received either a liver or cardiothoracic transplant, 9 took mycophenolate mofetil throughout pregnancy. Overall, 60% breastfed their infants, although the exact number who breastfed with mycophenolate or their outcomes were not reported.
An Australian case series reported 3 women with heart transplants who had a total of 5 infants, all of whom were breastfed (extent not stated). Two of the women took mycophenolate mofetil postpartum, one in a dosage of 720 mg twice daily and the other woman in a dosage of 1 gram twice daily. No adverse infant effects were reported up to the times of hospital discharge.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is mycophenolate?
Mycophenolate is a medication that has been used to treat some autoimmune conditions like rheumatoid arthritis and lupus. Mycophenolate may also be taken to help prevent the body from rejecting an organ, such as a kidney, after a transplant. Mycophenolate works by lowering the immune system (the body’s defense system against substances and germs that could be harmful). Mycophenolate is sold under the brand name Cellcept®. A similar medication called mycophenolic acid is sold under the brand name Myfortic®.For more information about rheumatoid arthritis and lupus, please see the MotherToBaby fact sheets at https://mothertobaby.org/fact-sheets/rheumatoid-arthritis/ and https://mothertobaby.org/fact-sheets/lupus-pregnancy/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I am taking mycophenolate, but I would like to stop taking it before getting pregnant. How long does the drug stay in my body?
People eliminate medication at different rates. In healthy adults, it takes up to one week, on average, for most of the mycophenolate to be gone from the body.
◈ I take mycophenolate. Can it make it harder for me to get pregnant?
It is not known if mycophenolate can make it harder to get pregnant.The U.S. Food and Drug Administration (FDA) requires that people who may become pregnant participate in a mycophenolate education program before they start taking the medication. Healthcare providers who prescribe mycophenolate must also participate in the program. The program requires having a negative pregnancy test before starting mycophenolate and another negative pregnancy test eight to ten days after treatment begins. The program also recommends using effective birth control to prevent pregnancy while taking mycophenolate. Birth control should continue for 6 weeks after stopping mycophenolate. It is important to know that mycophenolate might make hormonal birth control methods, like birth control pills, not work as well to prevent pregnancy.
◈ Does taking mycophenolate increase the chance for miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Taking mycophenolate in pregnancy can increase the chance of miscarriage. One report suggests the chance for miscarriage with mycophenolate use during pregnancy may be close to 50% (1 in every 2 pregnancies). Since some of the conditions that mycophenolate is used to treat can also increase the chance of miscarriage, it is hard to know if the medication, the medical condition, or other factors are the cause of a miscarriage.
◈ Does taking mycophenolate increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Taking mycophenolate during pregnancy might increase the chance of birth defects. A pattern of birth defects has been reported that includes unusually small or absent ears, eyes, and/or jaw; heart defects, cleft lip and/or palate (openings in the lip or the roof of the mouth), and others. Affected children might have only one birth defect or a combination of these birth defects. Not all children exposed to mycophenolate during pregnancy will have a birth defect.
◈ Does taking mycophenolate in pregnancy increase the chance of other pregnancy-related problems?
It is not known if mycophenolate can cause other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking mycophenolate in pregnancy affect future behavior or learning for the child?
It is not known if mycophenolate increases the chance for behavior or learning issues.
◈ What screenings or tests are available to see if my pregnancy has birth defects or other issues?
Prenatal ultrasounds can be used to screen for some birth defects, such as defects of the ears, eyes, jaw, heart, lip, and palate. Ultrasound can also be used to monitor the growth of the pregnancy. Talk with your healthcare provider about any prenatal screenings or testing that are available to you. There are no tests available during pregnancy that can tell how much effect there could be on future behavior or learning.
◈ Breastfeeding while taking mycophenolate:
It is not clear how much mycophenolate gets into breast milk. Limited reports of infants that have been exposed to mycophenolate through breastmilk have not reported harmful effects. Be sure talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes mycophenolate, could it affect fertility or increase the chance of birth defects?
Studies have not been done to see if mycophenolate could affect male fertility (ability to get partner pregnant). Three studies looking at 356 infants born to males taking mycophenolate around the time of conception found no increase in birth defects. Another report including 255 children born to males taking mycophenolate also showed no increase in miscarriage or birth defects.Due to theoretical concern (and not proven risks), some healthcare providers may recommend that males taking mycophenolate wait at least three months after stopping treatment before trying to conceive a pregnancy. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Mycophenolic acid is highly protein-bound, and more than 98% of it is bound to albumin.

[1]. Screening and Identification of Lujo Virus Inhibitors Using a Recombinant Reporter Virus Platform. Viruses. 2021 Jun 28;13(7):1255.

[2]. Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol Cancer Ther. 2008 Jun;7(6):1656-68.

Mycophenolic acid is a member of the class of 2-benzofurans that is 2-benzofuran-1(3H)-one which is substituted at positions 4, 5, 6, and 7 by methyl, methoxy, (2E)-5-carboxy-3-methylpent-2-en-1-yl, and hydroxy groups, respectively. It is an antibiotic produced by Penicillium brevi-compactum, P. stoloniferum, P. echinulatum and related species. An immunosuppressant, it is widely used (partiularly as its sodium salt and as the 2-(morpholin-4-yl)ethyl ester prodrug, mycophenolate mofetil) to prevent tissue rejection following organ transplants and for the treatment of certain autoimmune diseases. It has a role as an antineoplastic agent, an antimicrobial agent, an EC 1.1.1.205 (IMP dehydrogenase) inhibitor, an immunosuppressive agent, a mycotoxin, a Penicillium metabolite, an environmental contaminant, a xenobiotic and an anticoronaviral agent. It is a gamma-lactone, a member of phenols, a monocarboxylic acid and a member of 2-benzofurans. It is functionally related to a hex-4-enoic acid. It is a conjugate acid of a mycophenolate.
Mycophenolic acid is a potent immunosuppressant agent that inhibits de novo purine biosynthesis. It was derived from Penicillium stoloniferum, and has also shown antibacterial, antifungal and antiviral properties.. Mycophenolic acid is used in immunosuppressive regimens as part of a triple therapy that includes a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone. This regimen can be used in place of the older anti-proliferative [azathioprine] due to its stronger immunosuppressive potency. However, mycophenolic acid treatment is more expensive and requires therapeutic drug monitoring to optimize efficacy and minimize toxicity. Mycophenolic acid is available as enteric-coated tablets of delayed-release, in an effort to improve upper gastrointestinal adverse events by delaying mycophenolic acid release until it reaches the small intestine. [Mycophenolate mofetil], a prodrug of mycophenolic acid, is also prescribed to transplant recipients to prevent organ rejection.
Mycophenolic acid is an Antimetabolite Immunosuppressant.
Mycophenolate mofetil is an antimetabolite and potent immunosuppressive agent used as adjunctive therapy in prevention of allograft rejection and in the treatment of serious autoimmune diseases. Mycophenolate therapy can be associated with mild serum enzyme elevations and it has been linked to rare instances of clinically apparent liver injury.
Mycophenolic acid has been reported in Colletotrichum sublineola, Penicillium griseofulvum, and other organisms with data available.
Mycophenolic Acid is an antineoplastic antibiotic derived from various Penicillium fungal species. Mycophenolic acid is an active metabolite of the prodrug mycophenolate mofetil. Mycophenolic acid inhibits inosine monophosphate dehydrogenase (IMPDH), preventing the formation of guanosine monophosphate and synthesis of lymphocyte DNA that results in inhibition of lymphocyte proliferation, antibody production, cellular adhesion, and migration of T and B lymphocytes. Mycophenolic acid also has antibacterial, antifungal, and antiviral activities. (NCI04)
Mycophenolate is the morpholinoethyl ester of mycophenolic acid (MPA). As an immunosuppressive agent in vivo, the active metabolite mycophenolate reversibly inhibits inosine 5'-monophosphate dehydrogenase (IMPDH), an enzyme involved in the de novo synthesis of guanine nucleotides, thereby retarding T-cell and B-cell proliferation. MPA displays high lymphocyte specificity and cytotoxicity because lymphocyte metabolism is highly dependent on both salvage and de novo synthesis of guanine nucleotides. (NCI04)
Mycophenolic acid is an an immunosuppresant drug and potent anti-proliferative, and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of triple therapy including a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone. It is also useful in research for the selection of animal cells that express the E. coli gene coding for XGPRT (xanthine guanine phosphoribosyltransferase).
Compound derived from Penicillium stoloniferum and related species. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase (IMP DEHYDROGENASE). Mycophenolic acid exerts selective effects on the immune system in which it prevents the proliferation of T-CELLS, LYMPHOCYTES, and the formation of antibodies from B-CELLS. It may also inhibit recruitment of LEUKOCYTES to sites of INFLAMMATION.
See also: Mycophenolate Mofetil (active moiety of); Mycophenolate Sodium (has salt form); Mycophenolate Mofetil Hydrochloride (active moiety of) ... View More ...

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Drug Indication
Mycophenolic acid is an antimetabolite immunosuppressant indicated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in pediatric patients at least 5 years of age and older who are at least 6 months post kidney transplant. Mycophenolic acid is used in combination with cyclosporine and corticosteroids.

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Mechanism of Action
Mycophenolic acid is a selective noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), that blocks the conversion of inosine-5-phosphate and xanthine-5-phosphate to guanosine-5-phosphate. By inhibiting IMPDH, mycophenolic acid interferes with the _de novo_ pathway of guanosine nucleotide synthesis without incorporation into DNA. While other cell types are able to use salvage pathways, T- and B-lymphocyte proliferation is a mechanism heavily dependent on the _de novo_ synthesis of purines. Therefore, mycophenolic acid has potent cytostatic effects on T- and B- and lymphocytes. Mycophenolic acid also suppresses antibody formation by B-lymphocytes and prevents the glycosylation of lymphocyte and monocyte glycoproteins involved in intercellular adhesion to endothelial cells.

C23H31NO7

433.495

320.125

C, 63.73; H, 7.21; N, 3.23; O, 25.84

24280-93-1

Mycophenolic acid-d3;1185242-90-3;Mycophenolic acid sodium;37415-62-6;Mycophenolic acid-13C17;1202866-92-9

446541

White to off-white solid powder

1.3±0.1 g/cm3

611.6±55.0 °C at 760 mmHg

141°C

225.8±25.0 °C

0.0±1.8 mmHg at 25°C

1.585

2.92

2

6

6

23

486

0

O1C(C2=C(C(C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])C([H])([H])C(=O)O[H])=C(C(C([H])([H])[H])=C2C1([H])[H])OC([H])([H])[H])O[H])=O

RTGDFNSFWBGLEC-SYZQJQIISA-N

InChI=1S/C17H20O6/c1-9(5-7-13(18)19)4-6-11-15(20)14-12(8-23-17(14)21)10(2)16(11)22-3/h4,20H,5-8H2,1-3H3,(H,18,19)/b9-4+

(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoic acid

Mycophenolic acid; Mycophenolate mofetil; RS-61443; Myfortic; Cellcept

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~64 mg/mL (~199.8 mM)
Ethanol: ~32 mg/mL (~99.9 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.80 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 33.33 mg/mL (104.05 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)