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Mini Reviews in Medicinal Chemistry 2017Mycophenolic acid (MPA) possesses antibacterial, antifungal, antiviral, immunosuppressive and anticancer properties. It is a non-competitive and reversible inhibitor of... (Review)
Review
BACKGROUND
Mycophenolic acid (MPA) possesses antibacterial, antifungal, antiviral, immunosuppressive and anticancer properties. It is a non-competitive and reversible inhibitor of dehydrogenase inosine-5'-monophosphate (IMPDH). This compound belongs to the immunosuppressive drugs used for the prevention of both acute and chronic transplant rejection. Until now, two derivatives of MPA have been used clinically: mycophenolate mofetil (MMF, CellCept) and mycophenolate sodium (MPS, Myfortic). They cause, similar to MPA, although at lower degree, the side effects such as vomiting, abdominal pain, diarrhea, nausea, gastrointestinal, urogenital tract, blood or nervous system disorders. These drawbacks and glucuronidation of MPA in vivo limit the use of these compounds as pharmaceuticals. Therefore, research is still going on for more effective analogs that are less toxic to the organism and could improve the quality of life of patients.
CONCLUSION
In this review article, the authors present the synthesis of novel derivatives of mycophenolic acid, together with their initial biological investigations.
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Molecular Structure; Mycophenolic Acid
PubMed: 27903231
DOI: 10.2174/1389557516666161129160001 -
The Australasian Journal of Dermatology Feb 2015Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. It was later... (Review)
Review
Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. It was later used in the treatment of psoriasis. However due to its side-effect profile and fears over its carcinogenic potential it was abandoned. From the late 1990s a prodrug, mycophenolate mofetil (MMF), was developed and more recently, enteric-coated mycophenolate sodium (EC-MPS), both of which have gained increasing use in the field of dermatology for a variety of skin conditions. This review discusses the pharmacology, mechanisms of action, side-effects and current clinical applications in dermatology of MMF and EC-MPS.
Topics: Humans; Immunosuppressive Agents; Mycophenolic Acid; Skin Diseases
PubMed: 25557632
DOI: 10.1111/ajd.12259 -
Advances in Clinical Chemistry 2016Mycophenolic acid (MPA) is an immunosuppressant requiring therapeutic drug monitoring. Although immunoassays are commercially available, there is significant positive... (Review)
Review
Mycophenolic acid (MPA) is an immunosuppressant requiring therapeutic drug monitoring. Although immunoassays are commercially available, there is significant positive bias using this approach when compared to high-performance liquid chromatography or LC combined with mass spectrometry (LC/MS) or tandem mass spectrometry (LC/MS/MS). Positive bias is due to variable cross-reactivity of MPA acyl glucuronide with antibodies traditionally used in immunoassay formats. As can be expected, the magnitude of bias varies considerably. MPA strongly binds albumin and, as a result, disproportionate increases in free MPA occur in patients with uremia, hypoalbuminemia, and hepatic dysfunction. As such, monitoring free MPA poses additional challenges. Because MPA inhibits inosine monophosphate dehydrogenase, monitoring this enzyme may provide an alternative approach.
Topics: Drug Interactions; Drug Monitoring; Humans; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 27645819
DOI: 10.1016/bs.acc.2016.04.001 -
Therapeutic Drug Monitoring Dec 1995Validated high-performance liquid chromatographic (HPLC) methods have been developed for the reliable measurement in plasma of mycophenolate mofetil (MMF), mycophenolic... (Review)
Review
Validated high-performance liquid chromatographic (HPLC) methods have been developed for the reliable measurement in plasma of mycophenolate mofetil (MMF), mycophenolic acid (MPA), its pharmacologically active metabolite, and mycophenolic acid glucuronide (MPAG), the inactive and primary metabolite of MPA. Using these validated HPLC methods, the pharmacokinetic behavior of MMF has been characterized in renal transplant patients as part of double-blind randomized multicenter clinical trials. The analytical performance characteristics of the HPLC methods are described. Based on investigations of the metabolism of MMF in animals, normal volunteers, and renal transplant patients, it has been established that MMF is rapidly converted to MPA. MPAG is the primary urinary excretion product derived from MPA. In vitro binding studies have revealed that MPA is extensively bound to plasma proteins and that human serum albumin is the primary binding protein. Pharmacokinetic studies have revealed the following: (1) MPA exhibits enterohepatic circulation in humans as a result of biliary excretion of MPAG followed by MPA production in the gastrointestinal tract and the appearance of secondary MPA peaks in plasma; (2) chronic renal impairment produces little change in the clearance of MPA but a marked decrease in plasma MPAG clearance, with a consequent substantial increase in the circulating MPAG concentration; and (3) pharmacokinetic/pharmacodynamic (PK/PD) studies have revealed a good correlation between drug exposure (AUC) and the probability of rejection. The implications of the PK/PD studies for the development of TDM practices are discussed.
Topics: Antibiotics, Antineoplastic; Drug Monitoring; Humans; Mycophenolic Acid
PubMed: 8588242
DOI: 10.1097/00007691-199512000-00024 -
Mycophenolic acid in kidney transplant patients with diabetes mellitus: does the formulation matter?Transplantation Reviews (Orlando, Fla.) Jul 2011Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30%... (Review)
Review
Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30% to 50% of patients with type 1 or 2 diabetes and can influence oral drug absorption. Time-to-peak concentration of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) is longer in diabetic kidney transplant patients than patients without diabetes. By retaining gut contents in the stomach for longer, this could increase local GI toxicity in diabetic recipients due to an extended duration of exposure to MPA in the stomach. The enteric-coated mycophenolate sodium (EC-MPS) formulation delays the release of MPA until pH is higher than 5.5, such that absorption takes place more distally compared with MMF. Patient-reported outcomes data have been used to assess the effect of conversion to EC-MPS in maintenance kidney transplant patients with diabetes who were experiencing MMF-related GI symptoms. Results indicated that conversion leads to improved GI symptom burden despite higher MPA exposure under the EC-MPS regimen. Improved GI tolerance using EC-MPS has permitted maintenance of optimal MPA exposure in nondiabetic populations. Comparative trials to evaluate the GI symptom burden and maximum achieved MPA dosing using the EC-MPS and MMF formulations in de novo and maintenance diabetic kidney transplant recipients are merited.
Topics: Absorption; Administration, Oral; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gastric Emptying; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tablets, Enteric-Coated; Treatment Outcome
PubMed: 21530217
DOI: 10.1016/j.trre.2010.12.003 -
Annals of Clinical Biochemistry May 2002The immunosuppressive agent mycophenolate mofetil is a prodrug for the active compound mycophenolic acid. Following organ transplantation, it is used mostly in...
The immunosuppressive agent mycophenolate mofetil is a prodrug for the active compound mycophenolic acid. Following organ transplantation, it is used mostly in combination with other immunosuppressive drugs, but it has also been used as primary therapy. Although in the pivotal clinical studies the drug was given in fixed doses, there has been substantial interest in the measurement of mycophenolic acid in plasma as a guide to optimizing therapy. Data have emerged which indicate that the metabolism of the compound is more complex than was originally thought and that variability in exposure to the drug, assessed by area under the time-concentration curve, is an important determinant of efficacy. This article highlights basic pharmacokinetic and pharmacodynamic data for mycophenolic acid, which underlie the rationale for its measurement. These data are then set in the context of providing a routine service for the measurement of the drug with either of the analytical techniques currently available--immunoassay or high-performance liquid chromatography. There are a number of issues regarding the clinical interpretation of mycophenolic acid measurements which are yet to be resolved. Centres contemplating the introduction of such a service will need to keep abreast of a rapidly evolving literature.
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Immunoassay; Kidney Transplantation; Lung Transplantation; Mycophenolic Acid; Prodrugs; Time Factors
PubMed: 12038590
DOI: 10.1258/0004563021902035 -
Natural Product Research May 2020Mycophenolic acid (MPA) is a group of metabolite derived from several species of , which shows potent bioactivity. In this study, a new derivative of MPA compound named...
Mycophenolic acid (MPA) is a group of metabolite derived from several species of , which shows potent bioactivity. In this study, a new derivative of MPA compound named penicacid D (), was isolated from the marine derived fungus sp. SCSIO sof101, along with seven known compounds (). Their structures were elucidated based on the HR-ESI-MS and NMR data. Moreover, the H and C NMR data of compound and the C NMR data of compound are reported. Compounds , and exhibited weak activities against (clinical isolation number 100385570) and (clinical isolation number 100069).
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Escherichia coli; Fungi; Molecular Structure; Mycophenolic Acid; Penicillium; Spectrum Analysis
PubMed: 30760051
DOI: 10.1080/14786419.2018.1553881 -
Handbook of Experimental Pharmacology 2020The goal of immunosuppressive therapy post-transplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection while minimizing drug side...
The goal of immunosuppressive therapy post-transplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection while minimizing drug side effects. Most therapies alter immune response mechanisms but are not immunologically specific, and a careful balance is required to find the dose that prevents rejection of the graft while minimizing the risks of overimmunosuppression leading to infection and cancer. While this chapter because of space constraints focuses on immunosuppressive therapy in pediatric renal transplant recipients, many aspects can be applied on pediatric recipients of other solid organ transplants such as the liver and heart. The major maintenance immunosuppressive agents currently used in various combination regimens are tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine, everolimus, sirolimus, and glucocorticoids (steroids). Although data from adult renal transplantation trials are used to help guide management decisions in pediatric patients, immunosuppressive therapy in pediatric renal transplant recipients often must be modified because of the unique dosage requirements and clinical effects of these agents in children, including their impact on growth and development. The optimal immunosuppressive therapy post-transplant is not established. The goal remains to find the best combination of immunosuppressive agents that optimizes allograft survival by preventing acute rejection while limiting drug toxicities.
Topics: Adult; Child; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus
PubMed: 31820175
DOI: 10.1007/164_2019_331 -
Current Medical Research and Opinion Dec 2006Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation.... (Review)
Review
BACKGROUND
Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation. Conventionally, it is administered at a fixed dose without serial measurements of plasma concentrations of mycophenolic acid (MPA), the active metabolite. Recently, there has been an increased interest in therapeutic drug monitoring (TDM) of MMF therapy to optimize the benefit/risk index of the drug. Predose trough samples of MPA are considered most convenient and economic, thereby allowing an increased use of TDM in the transplant setting. However, the added value of TDM for MMF therapy is still under debate.
OBJECTIVE
This paper reviews (based on a systematic PubMed and EMBASE search, 1995-June 2006) the current evidence of the usefulness and clinical relevance of MPA trough level monitoring during MMF therapy in solid organ transplantation.
FINDINGS AND CONCLUSIONS
Based on data available in the public domain, the contribution of MPA trough level monitoring during MMF therapy in solid organ transplant recipients remains unproven. Available studies have limitations and report conflicting results. There is a lack of prospective randomized trials, particularly in pediatric renal transplant recipients and in cardiac and liver transplantation. While there is a suggestion that there may be a relationship between efficacy and MPA trough levels, the majority of studies showed no correlation between MPA plasma concentrations and adverse effects. Based on current evidence, the adherence to presently recommended target ranges for MPA troughs in solid organ transplantation cannot assure an improved clinical outcome with MMF therapy. Whether MPA trough level monitoring leads to improved efficacy and less toxicity is currently subject to a large randomized trial; final results are eagerly awaited.
Topics: Drug Monitoring; Humans; Immunosuppressive Agents; Mycophenolic Acid; Transplants
PubMed: 17257450
DOI: 10.1185/030079906X148481 -
Handbook of Experimental Pharmacology 2022Antiproliferative agents include Mycophenolic acid and Azathioprine (which is less commonly used unless in certain conditions). They were initially identified for use in...
Antiproliferative agents include Mycophenolic acid and Azathioprine (which is less commonly used unless in certain conditions). They were initially identified for use in autoimmune and cancer research due to their role in disruption of cellular replication. They have now become the cornerstone of antirejection maintenance therapy in solid organ transplant. In this chapter we will describe the major times that lead to discovery, mechanisms of action, side effects, use during pregnancy and the major clinical trials.
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 34697667
DOI: 10.1007/164_2021_556