Mycophenolic acid, chemical formula C17H20O6, is a milky white powder that is soluble in methanol and ethanol, slightly soluble in ether and chloroform, insoluble in benzene and toluene, and almost insoluble in cold water. Mycophenlic acid ester, as the main immunosuppressant, has been widely used at home and abroad to prevent and treat acute rejection of transplanted organs. Produced by fermentation metabolism of Penicillium Brevi compactum, it is an antibiotic with immunosuppressive effects. It was first isolated in 1896 and has activities such as anti-tumor, antiviral, immunosuppressive, anti psoriasis, and anti-inflammatory, with particularly prominent immunosuppressive activity. The bioavailability of mycophenlic acid is relatively low, and attempts have been made to improve the bioavailability and specificity of MPA by manufacturing its derivatives. Mycophenolate mofetil (MMF) and Mycophenolate sodium (MPS) are two important derivatives of Jatropha curcas, which were certified by the US FDA in 1998 and 2004. They are mainly used for the prevention and treatment of acute rejection reactions in organ transplantation. Mycophenolate mofetil is a derivative of MPA's 2-morpholinoethyl ester (Mycophenlic Acid) ester. MPA is a reversible inhibitor of xanthine monophosphate dehydrogenase I/II (IMPDH), which can non competitively bind to hypoxanthine mononucleotide dehydrogenase, a key enzyme involved in de novo synthesis of guanine nucleotides during T and B lymphocyte proliferation. MMF has been widely used in organ transplantation both domestically and internationally in clinical practice.
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Chemical Formula |
C17H20O6 |
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Exact Mass |
320 |
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Molecular Weight |
320 |
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m/z |
320 (100.0%), 321 (18.4%), 322 (1.6%), 322 (1.2%) |
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Elemental Analysis |
C, 63.74; H, 6.29; O, 29.97 |
Mycophenolic acid is a bioactive compound that can be used in medicine after esterification. It plays a key role in the de novo purine synthesis pathway as a non competitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Originally developed as a precursor drug for mycophenolate mofetil to improve its oral bioavailability. Mycophenolate mofetil, now commonly known as Mycophenolate mofetil (MMF), is an ester form of mycophenolate mofetil and has been widely used in clinical practice.
The application in the field of organ transplantation is one of its most important uses. After organ transplantation, foreign organs that do not belong to the original tissues of the human body can stimulate the immune system and cause local inflammation, leading to rejection reactions. By inhibiting the proliferation and activity of T and B cells, the immune system's attack is reduced, effectively preventing rejection reactions.
(1) Kidney transplantation: It is one of the preferred drugs for immunosuppressive therapy after kidney transplantation. It can significantly reduce the incidence of acute rejection and improve the survival rate of transplanted kidneys. In addition, it can also be used in combination with other immunosuppressants to enhance the immunosuppressive effect.
(2) Heart, lung, liver and other organ transplantation: In addition to kidney transplantation, it is also widely used for postoperative immunosuppressive therapy of heart, lung, liver and other organs. It can also reduce rejection reactions and improve the survival rate of transplanted organs.
Not only can it be used for immunosuppressive therapy after organ transplantation, but it can also be used to treat various autoimmune diseases. These diseases typically manifest as chronic illnesses that require long-term treatment and management.
Application in autoimmune diseases
(1) Systemic lupus erythematosus (SLE): It is an important medication in the treatment of SLE. It alleviates disease symptoms by suppressing the activity of the immune system and reducing the production of autoantibodies. In addition, it can also be used in combination with other drugs such as glucocorticoids to enhance the therapeutic effect.
(2) Sjogren's syndrome: Sjogren's syndrome is a chronic inflammatory autoimmune disease involving exocrine glands. It can improve symptoms such as dry mouth and eyes in patients by suppressing immune system attacks and reducing glandular damage.
(3) Rheumatoid arthritis: can also be used to treat rheumatoid arthritis. It improves the quality of life of patients by inhibiting the proliferation and activity of T and B cells, reducing joint inflammation and injury.
(4) Other autoimmune diseases: In addition to the above-mentioned diseases, it can also be used to treat various other autoimmune diseases, such as pemphigus vulgaris, refractory systemic lupus erythematosus, immunoglobulin A nephropathy, small vessel vasculitis, and psoriasis. The treatment of these diseases usually requires long-term medication and close monitoring of changes in the patient's condition.
In addition to immunosuppressive effects, it also has broad-spectrum effects such as antiviral, antifungal, antibacterial, and anticancer effects. These characteristics make it potentially valuable for the treatment of various diseases.
Antiviral, antifungal, antibacterial, and anticancer effects
(1) Antiviral effect: It can inhibit the replication and transmission of various viruses, including herpes virus, cytomegalovirus, etc. This makes it have potential application prospects in the treatment of viral infections.
(2) Antifungal effect: It also has inhibitory effects on certain fungi and can be used to treat infections caused by these fungi. However, it should be noted that its antifungal effect is relatively weak and usually needs to be used in combination with other antifungal drugs.
(3) Antibacterial effect: It also has inhibitory effects on certain bacteria, but its antibacterial spectrum is relatively narrow. Therefore, in the treatment of bacterial infections, it is usually used as an adjuvant therapy drug.
(4) Anti cancer effect: In recent years, research has found potential application value in the treatment of certain tumors. It exerts anti-cancer effects by inhibiting the proliferation and activity of tumor cells, inducing tumor cell apoptosis. However, further research and exploration are still needed regarding the specific application and efficacy in tumor treatment.
Absorb
Bullingham et al. believe that regardless of oral or intravenous administration, MMF can be rapidly and widely absorbed by the body and completely metabolized into its active product MPA before circulation. The Mycophenolic Acid administration time curves of the two routes of administration are basically similar. The average MPA peak time (tmax) is about 1 hour. The average half-life (t1/2) of MPA is about 17 hours, indicating that twice daily medication is more appropriate. There was no significant difference in the area under the concentration time curve (AUC ∞) of MPA between the two administration routes, which was approximately 105 mg/L.
Metabolize
MPA is metabolized by uridine diphosphate glucosyltransferase (UGT) to inactive mycophenolate glucuronide (MPAG). The liver is the most active organ for UGT and the main site for MPA metabolism.
Bullingham et al. found that within 1 hour after medication, the plasma concentration of MPAG was lower than the MPA concentration at the same time, but later it was several times higher. The average MPAGt1/2 is similar to MPA, while the total MPAGAUC is four to five times higher than MPA, and correspondingly, its average plasma clearance rate is four to five times lower than MPA. Comparing the early stages of MPAG and MPA graphics, the two have similar shapes, but the former is delayed and widened compared to the latter.
In the late 1990s, Shipkova et al. isolated two other metabolites of MPA from the blood of transplant recipients: mycophenlic acid acyl gluconic acid (AcMPAG) and mycophenlic acid phenyl gluconic acid (MPAG1s). MPAG1s have no inhibitory effect on IMPDH and do not participate in immune responses; In vitro experiments have shown that AcMPAG can inhibit recombinant human type II IMPDH (rh IMPDH-II) and suppress lymphocyte proliferation (3,4). On the other hand, AcMPAG can covalently bind to plasma proteins and other macromolecules, which is considered to be their immune and toxic mechanism.
Multidrug resistance associated protein 2 (MRP2) is expressed on the surface of liver cells, and its function is to excrete endogenous conjugates and drug metabolites into bile. Kobayashi et al. confirmed that the bile excretion of MPAG relies on MRP2 to complete. Free MPA (fMPA) is also a substrate for MRP2, but it seems that MRP2 prefers MPAG over MPA.
When bile enters the small intestine, MPAG is degraded into MPA under the action of microorganisms and reabsorbed into the systemic circulation. This process is known as the enterohepatic circulation (EHC) of MPA, which shows a second peak (smaller than the first peak) appearing 6-12 hours after administration on the drug time curve. It has been confirmed that EHC can increase MPA-AUC by an average of 37%.
Research has shown that the MPAEHC effect significantly affects the in vivo metabolism of MMF. Factors that affect bile secretion and excretion in the body, such as colitis, diarrhea, and antibiotics, can alter intestinal absorption function and/or the number of intestinal microbiota, all of which may cause significant changes in the in vivo metabolism of MMF.
Eliminate
MPAG is secreted and excreted into urine through renal tubules. Oral administration of radiolabeled MMF can fully recover the administered dose, with 93% occurring in urine and 6% in feces. Most of it is excreted in urine in the form of MPAG, and very small amounts are excreted in urine in the form of MPA.
Shaw et al. believe that three factors regulate MPA clearance rate: (1) UGT in the liver and gastrointestinal tract; (2)MPA-EHC; (3) MPA dissociation degree. Factors that can cause significant changes in MPA clearance rate or are related to it include acute or chronic renal insufficiency, concomitant immunosuppressants such as CsA and corticosteroids, and time after transplantation. Another possible factor is racial differences.
Free MPA
The binding rate of Mycophenolic Acid to albumin is about 97%, and stable transplant patients' fMPA accounts for 1-3% of the total MPA. The inhibition of IMPDH and the inhibition of mitogen stimulated lymphocyte proliferation depend on the concentration of fMPA. The characteristics of binding to albumin and patient factors can significantly alter fMPA and fMPA AUC. Shaw et al. believe that measuring free MPA concentration and total MPA concentration can help measure MPA exposure, and the following factors can significantly reduce the binding rate of MPA to albumin: (1) patients with early renal dysfunction after kidney transplantation; (2) Patients with chronic renal failure; (3) Early postoperative patients after liver transplantation; (4) Patients with low albumin and/or high bilirubin.
In a study of pediatric kidney transplantation, it was found that fMPA AUC is an important factor causing MMF related side effects, with an increased risk of leukopenia or infection when the dose is greater than 0.4 mg/L.
Mechanism of action:
MPA (mycophenolate mofetil or its active metabolite mycophenolate mofetil), as a highly efficient, selective, reversible, and non competitive inhibitor of inosine dehydrogenase (IMPDH), has shown extensive potential in the fields of biology and medicine. IMPDH is a key enzyme in the de novo synthesis pathway of purine nucleotides, responsible for catalyzing the conversion of xanthine monophosphate (IMP) to xanthine monophosphate (GMP) or adenosine monophosphate (AMP), which is a critical step in the synthesis of guanine nucleotides and adenine nucleotides. MPA effectively blocks the classical synthesis pathway of IMPDH by specifically inhibiting it, resulting in reduced supply of guanine nucleotides (such as GTP) and adenine nucleotides (such as ATP) within the cell.
The proliferation of T and B lymphocytes is highly dependent on de novo synthesis of purine nucleotides, and MPA significantly inhibits the proliferation of these cells by suppressing this process. It is worth noting that other types of cells, such as macrophages or fibroblasts, are typically able to rely on salvage pathways (i.e. utilizing exogenous purine nucleotides or bases) to synthesize the required purines, and therefore are less affected by MPA. This selective inhibitory effect makes MPA an effective therapeutic tool for regulating immune responses, especially against autoimmune diseases and transplant rejection. By blocking the de novo synthesis pathway of DNA in T and B lymphocytes, MPA exerts a strong immunosuppressive effect.
MPA (or MMF, also known as mycophenolate mofetil, the precursor drug of MPA) exhibits various non immunosuppressive biological activities. It can effectively inhibit the growth of mesangial cells and smooth muscle cells, which play an important role in a variety of pathological processes, such as glomerulonephritis, atherosclerosis, etc. By inhibiting the proliferation of these cells, MPA helps slow down the progression of the disease. At the same time, MPA can also inhibit the proliferation of vascular endothelial cells, which is a key step in the repair of blood vessels after injury and the formation of atherosclerosis, thus helping to maintain the normal structure and function of blood vessels.
MPA exerts anti-inflammatory effects by inhibiting the activity of adhesion molecules such as selectins, integrins, and members of the immunoglobulin superfamily, reducing the interaction between inflammatory cells and endothelial cells, lowering the recruitment and infiltration of inflammatory cells. This anti-inflammatory effect is of great significance for the treatment of various inflammatory diseases, such as glomerulonephritis and autoimmune hepatitis. In addition, by reducing the production of inflammation and fibrosis related factors, Mycophenolic Acid can effectively inhibit the process of tissue fibrosis, protect organ function, and improve the quality of life of patients.
Mycophenolic acid (MPA) is a natural product with significant pharmacological activity, initially isolated from fungi. As an immunosuppressant, it is widely used in anti rejection therapy after organ transplantation, and also exhibits various biological activities such as antiviral, anti-tumor, and anti-inflammatory effects. The discovery of MPA can be traced back to the late 19th century, when scientists began studying the metabolites of fungi. In 1893, Italian scientist Bartolomeo Gosio first isolated a substance with antibacterial activity from the culture medium of Penicillium fungi while studying it. Gosio discovered that the substance could inhibit the growth of Bacillus anthracis, but due to limitations in analytical techniques at the time, he was unable to fully identify its chemical structure. This substance was later confirmed to be MPA, but due to Gosio's research not being widely disseminated, the true discoverers of MPA are usually considered to be later researchers. At the beginning of the 20th century, with the development of microbiology and organic chemistry, scientists began to systematically study fungal metabolites. In 1913, American scientists Alsberg and Black isolated an acidic substance from the culture medium of Penicillium stolonifera and named it "mycophenolic acid", which means "phenolic acid produced by fungi". They have preliminarily described its antibacterial properties, but their precise structure has not yet been determined. The chemical structure identification of MPA has gone through a long process. In the 1940s and 1950s, with the development of chromatographic technology and spectroscopic analysis (such as ultraviolet, infrared, and nuclear magnetic resonance), scientists were able to more accurately analyze the structures of complex natural products. In 1945, British chemist Raistrick and his team conducted further research on MPA and proposed some of its structural features. In 1952, Birch and Donovan finally determined the complete structure of MPA through chemical degradation and synthesis experiments. MPA is a phenolic compound with a unique benzopyran skeleton and an enol ether side chain (Figure 1). This discovery laid the foundation for subsequent chemical modifications and drug development. After the structure of MPA was determined, scientists began to study its biological activity. Early studies found that MPA has antibacterial and antiviral effects, but its antibacterial spectrum is narrow, limiting its application in the treatment of infectious diseases. However, in 1969, scientists discovered that MPA could inhibit lymphocyte proliferation, suggesting that it may have immunosuppressive effects. In the 1970s, researchers further elucidated the mechanism of action of MPA. In 1977, Allison and colleagues discovered that MPA is a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is a key enzyme in guanine nucleotide synthesis, and the proliferation of T and B lymphocytes is highly dependent on this pathway. Therefore, MPA can selectively inhibit lymphocytes, reduce immune responses, and have little effect on other cells. This discovery provides a theoretical basis for the clinical application of MPA as an immunosuppressant.
Mycophenolic acid represents a paradigm shift in immunosuppressive therapy, combining targeted mechanism of action with versatile clinical applications. Ongoing research continues to expand its therapeutic frontier while addressing limitations through innovative formulations and precision dosing strategies. As the understanding of MPA's multi-faceted pharmacology deepens, this compound is poised to remain indispensable in transplantation and autoimmune medicine for decades to come.
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