Mycophenolic Acid

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 5103 Experts worldwide ranked by ideXlab platform

Leslie M. Shaw - One of the best experts on this subject based on the ideXlab platform.

  • the apparent inhibition of inosine monophosphate dehydrogenase by Mycophenolic Acid glucuronide is attributable to the presence of trace quantities of Mycophenolic Acid
    Clinical Chemistry, 1999
    Co-Authors: Magdalena Korecka, Dejan Nikolic, Leslie M. Shaw
    Abstract:

    Background: Mycophenolic Acid glucuronide, the primary metabolite of the immunosuppressive agent Mycophenolic Acid, affords weak inhibition of proliferating and resting lymphocytes and recombinant human inosine monophosphate dehydrogenase in comparison to the active drug. We evaluated the hypothesis that Mycophenolic Acid is a trace contaminant of the glucuronide metabolite preparation and that this accounts for the observed effects of Mycophenolic Acid glucuronide on human inosine monophosphate dehydrogenase catalytic activity both in lymphocytes and the pure enzyme. Methods: We used negative ion electrospray HPLC-mass spectrometry (HPLC-MS) and HPLC-tandem MS (HPLC-MS-MS) to identify Mycophenolic Acid as a contaminant of Mycophenolic Acid glucuronide. Quantification of the Mycophenolic Acid contaminant was achieved using a negative ion electrospray HPLC-MS method in the selected-ion monitoring mode. Results: Trace amounts of Mycophenolic Acid were detected and definitively identified in the Mycophenolic Acid glucuronide preparation by the HPLC-MS-MS analysis. In addition to having identical HPLC retention times, pure Mycophenolic Acid and the contaminant produced the following major fragments upon HPLC-MS-MS analysis: deprotonated molecular ion, m/z 319; and fragment ions, m/z 275, 243, 205, and 191 (the most abundant fragment ion). Using the negative ion electrospray HPLC-MS procedure in the selected-ion monitoring mode, the quantity of the contaminant Mycophenolic Acid was determined to be 0.312% ± 0.0184% on a molar basis. Conclusion: These data provide strong support for the proposal that the apparent inhibition of the target enzyme inosine monophosphate dehydrogenase by Mycophenolic Acid glucuronide is attributable to the presence of trace amounts of contaminant Mycophenolic Acid.

  • effect of Mycophenolic Acid glucuronide on inosine monophosphate dehydrogenase activity
    Therapeutic Drug Monitoring, 1997
    Co-Authors: Irena Nowak, Leslie M. Shaw
    Abstract:

    Mycophenolic Acid glucuronide (MPAG) inhibition kinetics were evaluated using purified recombinant human type II inosine monophosphate dehydrogenase (IMPDH). MPAG inhibitory concentrations (IC 50 ) were found to be 532- to 1022-fold higher than those for MPA. As expected, according to tight-binding inhibitor kinetics, Mycophenolic Acid (MPA) IC 50 values increased as IMPDH concentrations increased, whereas IC 50 values for xanthosine monophosphate (competitive IMPDH inhibitor used as a control), an inhibitor known not to be tight binding, remained independent of enzyme concentration. Although MPAG exhibited only weak inhibition of IMPDH activity, in comparison with MPA, IC 50 values increased with increasing enzyme concentration. The presence of trace quantities of MPA (0.2% on a molar basis) in the MPAG preparation, detected by high-performance liquid chromatography analysis, could account for this observation. These data support the proposal that MPAG is a pharmacologically inactive metabolite of MPA.

  • Mycophenolic Acid binding to human serum albumin characterization and relation to pharmacodynamics
    Clinical Chemistry, 1995
    Co-Authors: Irena Nowak, Leslie M. Shaw
    Abstract:

    Mycophenolate mofetil, the prodrug form of the immunosuppressive agent Mycophenolic Acid (MPA), is currently in clinical trials evaluating its effectiveness in transplant recipients. In this study, we validated an ultrafiltration system for the reliable measurement of free MPA. Using this technique, we evaluated factors that might be important in modulating the free fraction of this drug. Human serum albumin (HSA), high concentrations of the primary glucuronide metabolite of MPA, and sodium salicylate significantly affected MPA binding. For HSA the mean +/- SE binding capacity (Bmax) and the dissociation constant (Kd) were 1095 +/- 34 mumol/L and 12.98 +/- 0.93 mumol/L, respectively. The dose for 50% inhibition (IC50) of inosine monophosphate dehydrogenase isoform II by MPA increased 5.4-fold as the concentration of HSA added to the enzyme reaction mixture increased from 0 to 50 g/L (0-724 mumol/L). Furthermore, the IC50 MPA concentration for phytohemagglutinin A-stimulated human peripheral blood mononuclear cells increased 4.8-fold when incubations were performed in the presence of 10 g/L (145 mumol/L) HSA vs no added HSA. These data support the hypothesis that the pharmacological activity of MPA is a function of unbound drug concentration.

S E Tett - One of the best experts on this subject based on the ideXlab platform.

  • consensus report on therapeutic drug monitoring of Mycophenolic Acid in solid organ transplantation
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Dirk Kuypers, Yannick Le Meur, Marcelo Cantarovich, Michael Tredger, S E Tett, Burkhard Tonshoff, David W Holt, Jeremy R Chapman, Dario Cattaneo, Teun Van Gelder
    Abstract:

    With the increasing use of Mycophenolic Acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. Personalized immunosuppressive therapy requires better strategies for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed the clinical usefulness of therapeutic drug monitoring (TDM) of MPA in solid organ transplantation in a prospective way, and they have produced opposing results. To provide clinicians with an objective and balanced clinical interpretation of the current scientific evidence on TDM of MPA, a consensus meeting involving 47 experts from around the world was commissioned by The Transplantation Society and held in Rome on November 20 to 21, 2008. The goal of this consensus meeting was to offer information to transplant practitioners on clinically relevant pharmacokinetic characteristics of MPA, to rationalize the basis for currently advised target exposure ranges for MPA in various types of organ transplantation, and to summarize available methods for application of MPA TDM in clinical practice. Although this consensus report does not evaluate the final role of MPA TDM in transplantation, it seeks to examine the current scientific evidence for concentration-controlled dosing of MPA.

  • free Mycophenolic Acid should be monitored in renal transplant recipients with hypoalbuminemia
    Therapeutic Drug Monitoring, 2004
    Co-Authors: Bronwyn Atcheson, Paul J Taylor, Peter I Pillans, Carl M J Kirkpatrick, Stephen B Duffull, David W Mudge, David W Johnson, S E Tett
    Abstract:

    The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total Mycophenolic Acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as greater than or equal to3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin less than or equal to 31 g/L), clinicians should consider monitoring the free MPA concentration.

  • evaluation of limited sampling strategies for estimation of 12 hour Mycophenolic Acid area under the plasma concentration time curve in adult renal transplant patients
    Therapeutic Drug Monitoring, 2000
    Co-Authors: Charlene Willis, S E Tett, Paul J Taylor, Paul Salm, Peter I Pillans
    Abstract:

    Mycophenolate mofetil, the oral prodrug of Mycophenolic Acid, is indicated as immunosuppressive therapy after renal transplantation. To aid in the investigation of pharmacokinetic-pharmacodynamic relationships of Mycophenolic Acid in the clinical setting, limited blood sampling strategies have been proposed, and models from these developed, for the estimation of Mycophenolic Acid area under the concentration-time curve (AUC). In the current study, the authors investigated the predictive performance of six published models to estimate AUG. A total of 49 profiles from 25 renal transplant patients were used to test each model's performance against a full 14 time-paint AUG. A wide range of agreement was found when predicted AUCs were compared with full AUCs using linear regression analysis (range: r(2) = 0.499 to 0.836). Model 1, which uses 4 time-points over 6 hours, was found to be superior to all Ether models. The range of time-points used in this model takes into account patients with variable absorption. This model should be further tested on data sets from other centers. The relatively poor performance of the other models may be caused by their inability to describe the peak concentration in these patients. Caution is warranted when using limited sampling strategies on patients whose absorption of Mycophenolic Acid is altered, compared with those of the pharmacokinetic profiles from which the model was developed.

Toshio Suzuki - One of the best experts on this subject based on the ideXlab platform.

Teun Van Gelder - One of the best experts on this subject based on the ideXlab platform.

  • voclosporin a novel calcineurin inhibitor without impact on Mycophenolic Acid in patients with sle
    Nephrology Dialysis Transplantation, 2021
    Co-Authors: Teun Van Gelder, Robert B. Huizinga, Laura Lisk, Neil Solomons
    Abstract:

    Background An open-label phase 1 study was conducted to evaluate the effect of voclosporin on blood levels of Mycophenolic Acid (MPA, active moiety) and Mycophenolic Acid glucuronide (MPAG, pharmacologically inactive metabolite) following dosing with mycophenolate mofetil (MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. Methods MMF was orally administered at a dose of 1 g BID for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg BID for seven consecutive days (Day 1 to Day 7), starting in the evening of Day 1 and ending with the morning dose on Day 7. Dense PK blood samplings were collected pre-dose in the morning and from 0.25 to 12 hours post-morning doses. Analyses were derived by non-compartmental methods. Results In 24 patients, MPA exposure (Cmax and AUC0-12) was similar in the presence and absence of voclosporin, with treatment ratios of 0.94 and 1.09, respectively (Cmax: 16.5 μg/mL [Day 1] vs.15.8 μg/mL [Day 7], AUC0-12: 39.1 μg.h/mL [Day 1] vs. 40.8 μg.h/mL [Day 7]. MPAG exposure showed a small increase in the presence of voclosporin (12% for Cmax and 27% for AUC0-12). Combination therapy was well tolerated. Conclusions There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be given concomitantly without the need for dose adjustment.

  • explaining variability in Mycophenolic Acid exposure to optimize mycophenolate mofetil dosing a population pharmacokinetic meta analysis of Mycophenolic Acid in renal transplant recipients
    Journal of The American Society of Nephrology, 2006
    Co-Authors: Reinier M Van Hest, Ron A A Mathot, Mark D Pescovitz, Robert D Gordon, Richard D Mamelok, Teun Van Gelder
    Abstract:

    Large between- and within-patient variability has been observed in the pharmacokinetics of Mycophenolic Acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

  • cyclosporine interacts with Mycophenolic Acid by inhibiting the multidrug resistance associated protein 2
    American Journal of Transplantation, 2005
    Co-Authors: Dennis A Hesselink, Reinier M Van Hest, Ron A A Mathot, F Bonthuis, Willem Weimar, Ron W F De Bruin, Teun Van Gelder
    Abstract:

    In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower Mycophenolic Acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.

  • comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of Mycophenolic Acid
    Therapeutic Drug Monitoring, 2001
    Co-Authors: Teun Van Gelder, J Klupp, Markus J Barten, Uwe Christians, Randall E Morris
    Abstract:

    Mycophenolate mofetil (MMF) is almost completely absorbed from the gut and is rapidly de-esterified into its active drug, Mycophenolic Acid (MPA). The main metabolite is glucuronidated MPA (MPAG), which is excreted into bile and undergoes enterohepatic recirculation. Studies in healthy volunteers treated with cholestyramine show that interruption of the enterohepatic recirculation decreases MPA exposure by approximately 40%. Published data show a difference in Mycophenolic Acid plasma concentrations between kidney transplant recipients treated with MMF plus cyclosporine (CsA) and those treated with MMF plus tacrolimus (TRL). However, the interpretation of these data is complicated by interpatient differences in variables that may influence MMF pharmacokinetics (e.g., underlying disease, co-medication, and time since transplantation). To understand the influence of TRL and CsA on MMF pharmacokinetics (PK) more completely, the authors eliminated confounding variables in clinical studies by performing drug interaction studies in inbred rats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) were treated once daily with oral CsA (8 mg/kg), TRL (4 mg/kg), or placebo on days 0-6 before all rats began once-daily oral treatment with MMF (20 mg/kg) on day 7. Combined treatment with either MMF + CsA, MMF + TRL, or MMF + placebo was continued for 1 week (days 8-14). Thereafter, CsA and TRL treatments were stopped but MMF treatment was continued on days 14-21. Blood was sampled during the 24 hours subsequent to dosing on day 7 (after the first MMF dose), on day 14 (after multiple MMF doses) and on day 21 (after CsA/TRL washout). Rats in the MMF + TRL group and in the MMF + placebo group showed a second peak in the MPA-PK profiles consistent with enterohepatic recirculation of MPA. The MPA-PK profiles for the MMF + CsA-treated animals did not show a second MPA peak. On Day 14, the mean plasma MPA-AUC(0-24 hours) for the CsA-treated animals was significantly less than MPA exposures for rats in the MMF + TRL- and the MMF + placebo-treated groups. Furthermore, in contrast to results from other investigators, co-administration of CsA and MMF significantly increased MPAG-AUC(0-24 hours). Serum creatinines did not differ among rats in the three groups. CsA but not TRL decreased MPA plasma levels and increased MPAG-AUC(0-24 hours). These data suggest that CsA inhibits MPAG excretion into bile and offer an explanation for the well-known increased MPA exposure in organ transplant patients caused by conversion from CsA- to TRL-based immunosuppression.

Emmanuel Coton - One of the best experts on this subject based on the ideXlab platform.

  • individual and combined effects of roquefortine c and Mycophenolic Acid on human monocytic and intestinal cells
    World Mycotoxin Journal, 2016
    Co-Authors: Kevin Fontaine, Jerome Mounier, Emmanuel Coton, Nolwenn Hymery
    Abstract:

    Roquefortine C (ROC) and Mycophenolic Acid (MPA) are secondary metabolites produced by various fungal species. It is known that both ROC and MPA may co-occur in raw materials or food. However, to date there is a lack of information regarding their toxicity. In this study, ROC and/or MPA cytotoxicity was evaluated on human intestinal (Caco-2) and monocytic cell cultures (THP-1 and CD14+). After 48 h single mycotoxin exposure, viability tests showed that monocytes (THP-1 and CD14+) were more sensitive to ROC (inhibitory concentration 50% (IC50)=55 and 45 μM, respectively) than to MPA (IC50>780 μM). IC50 values determined from ROC and MPA mono-exposure experiments on Caco-2 cells were >100 and >780 μM, respectively. Caco-2 cell viability was significantly reduced after 48 h co-exposure at high ROC/MPA concentrations. A synergistic effect was observed at 10/78, 25/780 and 50/780 μM ROC/MPA concentrations, while an additive effect was seen at 100/780 μM. THP-1 apoptosis rate increased after 3 and/or 6 h single...

  • occurrence of roquefortine c Mycophenolic Acid and aflatoxin m1 mycotoxins in blue veined cheeses
    Food Control, 2015
    Co-Authors: Kevin Fontaine, Elena Passero, L Vallone, Nolwenn Hymery, Monika Coton, Jeanluc Jany, Jerome Mounier, Emmanuel Coton
    Abstract:

    Abstract Penicillium roqueforti , a food and feed contaminant, is known for its potential to produce roquefortine C (ROQC) and Mycophenolic Acid (MPA) amongst other mycotoxins. In blue-veined cheeses, selected P. roqueforti ripening cultures are used for organoleptic development but little is known about mycotoxin occurrence in these products. In this study, aflatoxin M1 (AFM1), ROQC and MPA levels were determined in 86 blue-veined cheeses collected worldwide using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). AFM1 was absent in all samples while 97.7% and 37.2% of cheeses contained quantifiable ROQC and MPA levels, respectively. Overall, the analyzed cheeses contained a large range of mycotoxin concentrations with ROQC and MPA mean levels at 848 ± 1670 μg/kg and 841 ± 1271 μg/kg, respectively. Noteworthy, 75% of cheese samples contained less than 792 μg/kg ROQC and 705 μg/kg MPA.

Mycophenolic Acid - 15 days free trial to Access Experts & Abstracts