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Toxicology Mechanisms and Methods Oct 2022The gastrointestinal side effects of mycophenolic acid affect its efficacy in kidney transplant patients, which may be due to its toxicity to the intestinal epithelial...
The gastrointestinal side effects of mycophenolic acid affect its efficacy in kidney transplant patients, which may be due to its toxicity to the intestinal epithelial mechanical barrier, including intestinal epithelial cell apoptosis and destruction of tight junctions. The toxicity mechanism of mycophenolic acid is related to oxidative stress-mediated, the activation of mitogen-activated protein kinases (MAPK). Schisandrin A (Sch A), one of the main active components of the Schisandra chinensis, can protect intestinal epithelial cells from deoxynivalenol-induced cytotoxicity and oxidative damage by antioxidant effects. The aim of this study was to investigate the protective effect and potential mechanism of Sch A on mycophenolic acid-induced damage in intestinal epithelial cell. The results showed that Sch A significantly reversed the mycophenolic acid-induced cell viability reduction, restored the expression of tight junction protein ZO-1, occludin, and reduced cell apoptosis. In addition, Sch A inhibited mycophenolic acid-mediated MAPK activation and reactive oxygen species (ROS) increase. Collectively, our study showed that Sch A protected intestinal epithelial cells from mycophenolic acid intestinal toxicity, at least in part, by reducing oxidative stress and inhibiting MAPK signaling pathway.
Topics: Apoptosis; Cyclooctanes; Humans; Intestinal Mucosa; Lignans; Mitogen-Activated Protein Kinases; Mycophenolic Acid; Oxidative Stress; Polycyclic Compounds; Tight Junctions
PubMed: 35321622
DOI: 10.1080/15376516.2022.2057263 -
Microbiology Spectrum Aug 2023Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the...
Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.026 to 0.89 μM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the postentry step to reduce the intracellular production of virions. Knockdown of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. This evidence shows that IMPDH is a potential target for the development of anti-MPXV agents. Mpox is a zoonotic disease caused by infection with the mpox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against mpox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against mpox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-mpox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited mpox virus propagation and exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested IMP dehydrogenase as a potential target for the development of anti-mpox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-mpox virus activity than mycophenolic acid.
Topics: Guanosine; IMP Dehydrogenase; Mycophenolic Acid; Trifluridine; Monkeypox virus
PubMed: 37409948
DOI: 10.1128/spectrum.00566-23 -
Biotechnology and Bioengineering Dec 2022Microorganisms are known to produce pharmaceutically important secondary metabolites that are used as drug moieties in the treatment of various disorders. Discovery of... (Review)
Review
Microorganisms are known to produce pharmaceutically important secondary metabolites that are used as drug moieties in the treatment of various disorders. Discovery of one such class of drugs called immunosuppressants led the way for new and improved treatment regimens for the cases of organ rejections as well as for autoimmune diseases. Uncovering the role of these secondary metabolites as immunomodulators had increased their demand in the global drug market. However, this was soon overshadowed by the low amount of product obtained after fermentation and tedious downstream processing for the recovery of product. Hence, continuous efforts are being made to enhance their production by unveiling the basic biosynthetic pathways involved in their synthesis. From unearthing these immunosuppressants to their rapid development towards commercialization, these drugs have gained a significant place in the world market. Hence, the present review is focused on the progress and challenges in the production and downstream processing of different immunosuppressants (tacrolimus, cyclosporine, rapamycin, and mycophenolic acid). This is the first review report on how the market demand of immunosuppressants could be fulfilled by exploring biofoundry approaches to achieve the goal.
Topics: Immunosuppressive Agents; Tacrolimus; Mycophenolic Acid; Cyclosporine; Sirolimus
PubMed: 36110089
DOI: 10.1002/bit.28231 -
Transplantation Proceedings Nov 2021The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and...
BACKGROUND
The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression.
METHODS
We studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B).
RESULTS
We analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P = .003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P = .006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group.
CONCLUSION
The use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients.
Topics: Edema; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus
PubMed: 34620498
DOI: 10.1016/j.transproceed.2021.07.053 -
Pharmacology Research & Perspectives Dec 2022The results of the previous studies demonstrated an association between mycophenolic acid (MPA) exposure, serum albumin level (ALB), and adverse effects in kidney...
The results of the previous studies demonstrated an association between mycophenolic acid (MPA) exposure, serum albumin level (ALB), and adverse effects in kidney transplant patients. The aim was the identification of mathematical correlation and association between both, total and unbound MPA concentration in relation to ALB, body mass (BM), age and estimated glomerular filtration rate (eGFR) in stable kidney transplant recipients. Furthermore, investigation was conducted with the aim to clarify the role of salivary concentration (C ) of MPA in adverse effect profile. In order to analyze the association between total and salivary concentration of MPA in relation to ALB, BM, age and eGFR, a least squares method for determining the correlation between these parameters was performed. In addition, derived mathematical model based on experimental data can also be performed and simulated through the Monte Carlo (MC) approach. Adverse effects were grouped according to the nature of symptoms and scored by a previously published validated system. Numerically calculated values of C from the models [C = f(ALB, BM, age, eGFR, C ) = a + a *(ALB, BM, age, eGFR) + a *C ] were then compared with those from validation set of patients, where the best fitting model was for ALB [C = 54.96-1.64*ALB +13.4*C ]. Adverse effects estimation showed the difference in esthetic score, positively correlated with C in the lower ALB group (145.41 ± 219.02 vs. 354.08 ± 262.19; with statistical significance p = .014) and almost significant for gastrointestinal score (167.69 ± 174.79 vs. 347.55 ± 320.95; p = .247). The study showed that C MPA may contribute to management of adverse effects, but these findings require confirmation of clinical utility.
Topics: Humans; Mycophenolic Acid; Immunosuppressive Agents; Kidney Transplantation; Glomerular Filtration Rate; Transplant Recipients
PubMed: 36440680
DOI: 10.1002/prp2.1034 -
Clinical Pharmacology and Therapeutics Jul 2023Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the...
Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C ) and abbreviated area under the curve from zero to 12 hours (AUC ) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30-0.50, P < 0.001), Tac-C (HR: 0.46, 95% CI: 0.38-0.57, P < 0.001) and MPA-AUC at 1 year (HR: 0.80, 95% CI: 0.68-0.94, P = 0.006), as well as repeated measurements of Tac-C (HR: 0.70, 95% credibility interval (CrI): 0.61-0.82, P < 0.001), and of MPA-AUC (HR: 0.75, 95% CrI: 0.62-0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC at 1 year would be 75-95 ng*hour/mL and a Tac-C 5-7 ng/mL. The Tac-AUC predicted BPAR better than Tac-C and identified KTRs with over- or underexposure despite supposedly adequate Tac-C . We did not find evidence to recommend another target than the consensus range of 30-60 mg*hour/L for MPA-AUC after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.
Topics: Humans; Tacrolimus; Mycophenolic Acid; Immunosuppressive Agents; Kidney Transplantation; Graft Rejection
PubMed: 37082913
DOI: 10.1002/cpt.2915 -
Xenobiotica; the Fate of Foreign... 20231. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of...
1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients.2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen.3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.
Topics: Adult; Humans; Mycophenolic Acid; Immunosuppressive Agents; Kidney Transplantation; Administration, Oral; China; Models, Biological
PubMed: 37991412
DOI: 10.1080/00498254.2023.2287168 -
Scientific Reports Mar 2023Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively...
Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF's active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.
Topics: Animals; Mice; Actin Cytoskeleton; Cell Survival; Cycloheximide; Mycophenolic Acid; Podocytes
PubMed: 36922538
DOI: 10.1038/s41598-023-31326-z -
Clinical Pharmacokinetics Dec 2019Mycophenolic acid is commonly prescribed in adult kidney transplant recipients for preventing graft rejection. A therapeutic target for total mycophenolic acid area... (Review)
Review
Mycophenolic acid is commonly prescribed in adult kidney transplant recipients for preventing graft rejection. A therapeutic target for total mycophenolic acid area under the concentration-time curve (30-60 mg h/L) has been established in adult kidney transplant recipients and widely referenced today. However, this specific target range does not adequately characterize mycophenolic acid-associated adverse effects. The primary objective of this qualitative and critical review was to characterize the exposure-toxicity relationships of mycophenolic acid in an attempt to determine whether exposure thresholds can be identified. The secondary objective was to determine the associations of clinical variables with specific adverse effects. The inclusion criteria consisted of all peer-reviewed papers in adult kidney transplant subjects (average study age > 18 years) with both exposure (area under the concentration-time curve) and toxicity data. The exclusion criteria were papers involving the pediatric population, studies lacking either area under the concentration-time curve or toxicity data, or studies with no apparent reported variations in area under the concentration-time curves. Of the 28 papers identified, inconsistent findings have been reported for the most frequently characterized adverse events of mycophenolic acid (gastrointestinal, infectious, and hematological), while promising exposure thresholds (i.e., > 40-60 mg h/L for total mycophenolic acid) have been suggested by a few studies. The roles of free mycophenolic acid exposure, mycophenolic acid metabolites, or clinical factors influencing the manifestation of the toxicities also remain to be clarified. Although it is not yet possible to define toxicity threshold(s) for the purpose of mycophenolic acid therapeutic drug monitoring, the information obtained and the limitations identified in this comprehensive literature body have provided a good foundation for future investigations.
Topics: Adult; Area Under Curve; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 31332670
DOI: 10.1007/s40262-019-00802-z -
Toxicological Sciences : An Official... Feb 2020Mycophenolic acid (MPA) is commonly prescribed for preventing graft rejection after kidney transplantation. The primary metabolic pathways of MPA are hepatic...
Mycophenolic acid (MPA) is commonly prescribed for preventing graft rejection after kidney transplantation. The primary metabolic pathways of MPA are hepatic glucuronidation through UDP-glucuronosyltransferase (UGT) enzymes in the formation of MPA-glucuronide (MPAG, major pathway) and MPA-acyl glucuronide (AcMPAG). p-Cresol, a potent uremic toxin known to accumulate in patients with renal dysfunction, can potentially interact with MPA via the inhibition of glucuronidation. We hypothesized that the interaction between MPA and p-cresol is clinically relevant and that the estimated exposure changes in the clinic are of toxicological significance. Using in vitro approaches (ie, human liver microsomes and recombinant enzymes), the potency and mechanisms of inhibition by p-cresol towards MPA glucuronidation were characterized. Inter-individual variabilities, effects of clinical co-variates, in vitro-in vivo prediction of likely changes in MPA exposure, and comparison to other toxins were determined for clinical relevance. p-Cresol inhibited MPAG formation in a potent and competitive manner (Ki=5.2 µM in pooled human liver microsomes) and the interaction was primarily mediated by UGT1A9. This interaction was estimated to increase plasma MPA exposure in patients by approximately 1.8-fold, which may result in MPA toxicity. The mechanism of inhibition for AcMPAG formation was noncompetitive (Ki=127.5 µM) and less likely to be clinically significant. p-Cresol was the most potent inhibitor of MPA-glucuronidation compared with other commonly studied uremic toxins (eg, indole-3-acetic acid, indoxyl sulfate, hippuric acid, kynurenic acid, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) and its metabolites (ie, p-cresol sulfate and p-cresol glucuronide). Our findings indicate that the interaction between p-cresol and MPA is of toxicological significance and warrants clinical investigation.
Topics: Cresols; Glucuronides; Glucuronosyltransferase; Microsomes, Liver; Mycophenolic Acid; Sulfuric Acid Esters; UDP-Glucuronosyltransferase 1A9
PubMed: 31742356
DOI: 10.1093/toxsci/kfz231