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At least 19 recordsLinked to original sources
PubMed2004

HPLC determination of mycophenolic acid and mycophenolic acid glucuronide in human plasma with hybrid material.

Mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil is an immunosuppressive agent which inhibits inosine monophosphate dehydrogenase. MPA is metabolised to phenolic glucuronide (MPAG) that may be hydrolysed in vivo to form free MPA. Drug monitoring is required in patients with multi-organ failure. Here, we report a HPLC method with organic/inorganic hybrid material for the simultaneous analysis of MPA and MPAG in human plasma. MPA and MPAG and carboxy butoxy ether mycophenolic acid (MPAC) used as internal standard were analysed on a bonded X-Terra column with a linear gradient elution mode using orthophosphoric acid and acetonitrile as eluents. Sample treatment procedure consists of deproteinisation with acetonitrile. Analytical recoveries were higher than 98 and 89% at concentrations ranging from 1 to 25 and 20 to 200mg/L for MPA and MPAG, respectively. Calibration curves fitted by plotting the peak area ratio (compound of interest/internal standard) versus concentration were linear in the range 0.2-50mg/L for MPA and in the range 1-500mg/L for MPAG. The quantification limit was 0.2mg/L for MPA and 1mg/L for MPAG with a coefficient of variation less than 20% for a 500microL sample volume. Intra- and inter-assay coefficient of variation was lower than 7% for all compounds. Detection was performed at 215nm. Peak identity was confirmed through library matching by comparison with reference spectra. The X-Terra column provides good peak shape and may be used at low pH with a long life-time column. This HPLC method using a simple sample treatment procedure appears suitable for therapeutic drug monitoring in organ-transplant patients. The method is sensitive enough for monitoring MPA and MPAG during pharmacokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed1999

A simple HPLC method for simultaneous determination of mycophenolic acid and mycophenolic acid glucuronide in plasma.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of mycophenolic acid and its metabolite, mycophenolic acid glucuronide, is presented herein. Sample purification is limited to protein precipitation with acetonitrile. The analytes were separated on a C18 column with a mobile phase containing 30% acetonitrile and a 40 mm phosphoric acid buffer at pH 2.1 and measured with UV-detection at 215 nm.

Chromatography, High Pressure Liquid↗
PubMed2002

Mycophenolic acid and mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: effect of cyclosporine and tacrolimus comedication.

Determinants of the wide interindividual variability of the pharmacokinetics of mycophenolic acid (MPA) in 21 stable pediatric liver transplant recipients were investigated in relation to the kinetics of the drug's major phenolic glucuronide metabolite (MPAG), cyclosporin (CsA), or tacrolimus (Tac) co-medication and liver and renal function. Trough concentrations (C(0) ) most reliably predicted the area under the curve (AUC) of 0-7 hours MPA plasma concentrations (r (2) = 0.650). Co-medication with CsA demanded higher MPA mofetil (MMF) doses to achieve equivalent trough levels than Tac (362 vs. 178 mg per mg/L, P= 0.004). Median MPA C(0) (range) was significantly lower during CsA co-therapy when corrected for MMF dose (2.8 vs. 5.6 mg MPA/L for Tac, P= 0.006). The AUC of MPAG was correspondingly higher during CsA co-medication (229 vs. 94 mg/L/h for Tac, P = 0.012) with the MPA-to-MPAG ratio at C(0) correspondingly lower (0.10 vs. 0.14, respectively, P = 0.04). This suggested contrasting effects of CsA and Tac on MPA glucuronidation or its excretion and enterohepatic recirculation. MPAG AUC was correlated to body weight and creatinine clearance. Children with elevated aspartate transaminase (AST; but with no evidence of rejection on liver biopsy, n = 7) had significantly lower MPA trough levels compared with those in whom AST was normal (0. 77 vs. 1.76 mg/L, P = 0.05), but there was no difference in the MMF dose per body weight. Examination of the MPA profiles in these subjects showed significantly lower MPA concentrations from 120 minutes after dose until the end of the 7-hour profile and suggest an accelerated clearance or decreased enterohepatic recirculation.)

Adolescent↗
PubMed1997

IMP-dehydrogenase inhibition in human lymphocytes and lymphoblasts by mycophenolic acid and mycophenolic acid glucuronide.

Inosine 5'-monophosphate dehydrogenase (IMP-DH) activities were measured in human lymphocytes (exhibiting type I IMP-DH activity) and human lymphoblasts (exhibiting type II IMP-DH activity) in the presence of various amounts of mycophenolic acid (MPA) (0-20 mumol/L) and MPA glucuronide (MPAG) (0-200 mumol/L). Moreover, the influences of human serum albumin (HSA) and human plasma on the MPA- and MPAG-mediated effects were investigated. In the presence of water, 2.5 mumol/L MPA decreased the IMP-DH activity measured in lymphocytes by 60%, whereas in lymphoblasts a 80% inhibition was detectable. In the presence of > or = 10 mumol/L MPA, lymphocytic as well as lymphoblastic IMP-DH activities were reduced in a similar manner. The concentration of MPAG required for 50% inhibition was for both cell types > 25 mumol/L and < 50 mumol/L, respectively. MPAG (200 mumol/L) reduced lymphocytic as well as lymphoblastic IMP-DH activity by approximately 80%. With 100 g/L HSA or human plasma as diluent, the inhibitory effects of MPA and MPAG were significantly (P < 0.05) diminished, whereas HSA concentrations < or = 25 g/L only slightly influenced the inhibition of IMP-DH activity by MPA and MPAG. In summary, it can be clearly demonstrated that not only MPA but also MPAG contributes to the inhibition of both IMP-DH isoenzymes, which might be relevant for the immunosuppressive properties of mycophenolate mofetil in transplant patients.

Blood Proteins↗
PubMed2000

Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid.

Mycophenolic acid, the active metabolite of the immunosuppressant and antiproliferative agent, mycophenolate mofetil, is primarily metabolized by glucuronidation to the inactive 7-O-glucuronide. Although the uridine diphosphate (UDP) 7-O-glucuronide is the principal excretion product of this drug, carboxyl-linked glucuronides have also been detected in vitro and in vivo. To identify human UDP glucuronosyltransferases that are active in the glucuronidation of mycophenolic acid, cDNAs encoding individual UDP glucuronosyltransferase forms have been expressed in cell culture, and the capacity of the expressed enzymes to use mycophenolic acid as a substrate has been assessed. Two UDP glucuronosyltransferase forms, UGT1A8 and UGT1A10, were active in the glucuronidation of mycophenolic acid. Both enzymes are predominantly expressed in the gastrointestinal tract and hence, may play a role in the metabolism of mycophenolic acid in the gastrointestinal tract and in the acquisition of resistance to the mito-inhibitory effects of this drug in cultured human colorectal carcinoma cell lines. The identities of the UDP glucuronosyltransferase forms that are mainly responsible for the glucuronidation of mycophenolic acid in the liver and kidney remain unknown; however, UGT1A9 may be important in this respect as the cDNA-expressed enzyme has some capacity to glucuronidate mycophenolic acid. Other UGT1A forms in the liver and kidney (UGT1A1, UGT1A3, UGT1A4, and UGT1A6) were inactive toward mycophenolic acid.

Glucuronides↗
PubMed1994

Pharmacodynamics of the inhibition of GTP synthesis in vivo by mycophenolic acid.

Mycophenolic acid is effective against a wide range of experimental tumors in rodents when given orally, despite rapid metabolism to the inactive glucuronide derivative and rapid clearance from plasma. In the light of this, the pharmacodynamic action of mycophenolic acid on the radiolabelling of GTP and ATP by [14C]hypoxanthine in spleen and heart has been investigated in vivo in the rat as a preliminary to studies in tumor tissue. The data indicate that inhibition of GTP, and more surprisingly, ATP synthesis in spleen was sustained for at least 24.25 hr after single oral doses of the disodium salt of mycophenolic acid, indicating that the inhibitor is retained in sensitive cells for considerably longer than might be expected from the pharmacokinetic profile in the plasma in this species. GTP and ATP levels became depressed in rat spleen subsequent to the inhibition of nucleotide radiolabelling. The persistence of mycophenolic acid in proliferating cells may account for the effectiveness of once daily dosing against rapidly growing experimental tumors. In contrast with spleen, there was no incorporation of radiolabel from [14C]hypoxanthine into either GTP or ATP in rat heart and mycophenolic acid had no effect on the cardiac content of either nucleotide. The lack of effect of mycophenolic acid on cardiac GTP levels is consistent with the absence of any pharmacological action on cardiac functions associated with receptor-G-protein-GTP interactions. The ability of the morpholinoethyl ester of mycophenolic acid (a clinically effective immunosuppressive agent) to inhibit GTP synthesis and depress GTP levels in rat spleen in vivo was compared with that of mycophenolic free acid and its disodium salt. The ester derivative was clearly more effective than the poorly water-soluble free acid but showed comparable activity with the freely soluble disodium salt.

Adenosine Triphosphate↗
PubMed1977

Lack of effect on cyclic GMP content of cells treated with mycophenolic acid.

Mycophenolic acid, an oncolytic agent and a known inhibitor of guanine ribonucleotide synthesis, has proven to be an effective drug against psoriasis. With reports of greater guantities of c-GMP in psoriatic tissues than in normal tissue, and with the correlation of c-GMP content of cells to proliferation, the effect of mycophenolic acid on cellular c-GMP was investigated. When HeLa, green monkey BSC-1, and mouse L-cells were treated with inhibitory concentrations of mycophenolic acid, no decrease in c-GMP was observed from that of untreated cells. Though mycophenolic acid inhibits guanine ribonucleotide synthesis, this inhibition does not extend to c-GMP synthesis. The inhibition of proliferation of cells by mycophenolic acid then does not include the inhibition of synthesis of c-GMP, but apparently resides solely in limiting the guanylate necessary for nucleic acid synthesis.

Cell Count↗
PubMed1975

Antitumor agents II: nitrogen analogs of mycophenolic acid.

Mycophenolic acid, a novel antibiotic of low toxicity containing no nitrogen atoms in its structure, induces tumor regression in several murine solid tumor assays. It has been reported in extensive structure-activity studies that chemical modifications on the antibiotic itself reduce or eliminate antitumor activity. With the objective of antitumor activity enhancement, nitrogen-containing analogs of mycophenolic acid were synthesized according to a program directed toward the ultimate synthesis of close bioisosteres of the antibiotic. Intial efforts reported here describe the terpenoid side-chain degradation of N-geranyl-2(1H)-pyridones and N-geranylglutarimides, where the terminal isopropylidene is replaced with a carboxyl group as it occurs in mycophenolic acid. The resulting nitrogen-containing analogs of the antitumor antibiotic were inactive in the l-1210 and Walker 256 tumor systems.

Aldehydes↗
PubMed1986

IMP dehydrogenase from the intracellular parasitic protozoan Eimeria tenella and its inhibition by mycophenolic acid.

Mycophenolic acid (MA) was demonstrated to be an effective inhibitor of the growth of the intracellular parasitic protozoan Eimeria tenella in tissue culture and guanine was shown to reverse this inhibition as expected for an inhibitor of IMP dehydrogenase (IMP:NAD+ oxidoreductase, EC 1.1.1.205). A high performance liquid chromatography study of the intracellular nucleotide pools labeled with [3H]hypoxanthine was carried out in host cells lacking hypoxanthine-guanine phosphoribosyltransferase, and the depletion of guanine nucleotides demonstrated that the intracellular parasite enzyme was being inhibited by the drug. Kinetic studies carried out on the enzyme derived from E. tenella oocysts demonstrated substrate inhibition by NAD and mycophenolic acid inhibition similar to that found for mammalian enzymes, but different from that for bacterial enzymes. The inhibition by mycophenolic acid was not time-dependent and was immediately reversed upon dilution. As found previously for other IMP dehydrogenases, an Ordered Bi-Bi mechanism prevails with IMP on first followed by NAD, NADH off first, and then XMP. The kinetic patterns are consistent with substrate inhibition at high concentrations of NAD due to the formation of an E X XMP X NAD complex. Uncompetitive inhibition by MA versus IMP, NAD, and K+ was found and this was interpreted as evidence for the formation of an E X XMP X MA complex. A speculative mechanism for the inhibition of the enzyme is offered which is consistent with the fact that E X XMP X MA readily forms, whereas E X IMP X MA does not.

Animals↗
PubMed2001

Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid.

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.

Animals↗
PubMed2006

Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid.

Mycophenolic acid (MPA) is the active immunosuppressive metabolite of the anti-organ rejection drug mycophenolate mofetil (MMF) and is implicated in the gastrointestinal toxicity associated with MMF therapy. Intestinal UDP-glucuronosyltransferases (UGT) have been proposed to provide intrinsic resistance against MMF-induced gastrointestinal toxicity by converting MPA to the inactive MPA 7-O-glucuronide. Using an optimized intestinal microsome preparation method that stabilized the intestinal MPA UGT activity, the MPA UGT activity of male Sprague-Dawley rat intestinal microsomes was characterized. A longitudinal gradient similar to that described for other phenolic compounds was observed, with the activity decreasing from the duodenum to the distal small intestine and colon. The catalytic efficiency of MPA glucuronidation decreased from the proximal to distal intestine as a result of decreasing Vmax and increasing Km. The finding that homozygous Gunn rats lack detectable intestinal MPA UGT activity indicates exclusive roles of UGT1A1, UGT1A6, and/or UGT1A7. Quantitative immunoblotting revealed a parallel between the MPA UGT activity and the content of UGT1A7-like immunoreactivity (18.7 and 7.3 microg/mg for duodenum and colon, respectively). In contrast, the lesser MPA-metabolizing UGT, UGT1A1 and UGT1A6, were lower in abundance (1.6-2.1 and 1.7-2.9 microg/mg, respectively), and their patterns of longitudinal distribution were distinct from the MPA UGT activity. These data suggest a dominant role of a UGT1A7-like enzyme, presumably UGT1A7 itself, in the catalysis of rat intestinal MPA glucuronidation. Studies are ongoing to investigate the relationship between intestinal UGT1A enzymes and susceptibility to MMF-induced gastrointestinal toxicity.

Animals↗
PubMed2006

Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid.

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a standard immunosuppressive drug approved for clinical use in the prevention of acute allograft rejection after organ transplantation. This study examines the role of the genetic variants of UDP-glucuronosyltransferase (UGT) 1A8 and 2B7 enzymes involved in the formation of the primary metabolite of MPA, the inactive phenolic glucuronide (MPAG), and the reactive acyl glucuronide (AcMPAG). The first exon of UGT1A8 was first resequenced in the region encoding for the substrate binding domain in 254 Caucasians and 41 African Americans. Eight nonsynonymous changes were observed and led to the following amino acid substitutions: S43L, H53N, S126G, A144V, A173G, A231T, T240A, and C277Y. Thirteen haplotypes were inferred, comprising only two previously described alleles, namely, UGT1A8*2 (A173G) and UGT1A8*3 (C277Y). Upon stable expression in human embryonic kidney 293 cells, the UGT1A8*3 (C277Y), *5 (G173A240), *7 (A231T), *8 (S43L), and *9 (N53G) proteins were associated with the most profound decreases in the formation of MPAG and AcMPAG, indicating that these amino acids are critical for substrate binding and enzyme function. Altogether, the low-activity UGT1A8 enzymes are carried by 2.8 to 4.8% of the population. The variant of the UGT2B7 protein (UGT2B7*2 Y268), the main enzyme involved in the formation of AcMPAG, demonstrated a catalytic efficiency comparable with that of UGT2B7*1 (H268). In conclusion, although the common UGT2B7*2 variant is predicted to have limited impact, several UGT1A8 variants identified may potentially account for the large interindividual variance in MMF pharmacokinetics and deserve further clinical investigations.

Acylation↗
PubMed2006

Antifibrotic actions of mycophenolic acid.

Mycophenolic acid (MPA) is a highly selective, non-competitive and reversible inhibitor of the inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides. Mycophenolate mofetil (MMF, the ester prodrug of MPA) strongly inhibits both T- and B-lymphocyte proliferation and has now been widely used in the prevention of acute and chronic allograft rejection. Recent evidence, however, suggests that MMF is also capable of inhibiting the proliferation of non-immune cells. In various cell lines, e.g. smooth muscle cells, renal tubular cells, mesangial cells, and fibroblasts, MPA reduced or even abrogated proliferation in response to proliferative stimuli. In animal studies, MMF ameliorated renal lesions in immune-mediated disease, e.g. in the Anti-Thy 1.1 model and experimental lupus nephritis, but was also effective in non-immune-mediated renal damage, e.g. in the rat remnant kidney model or in a model of chronic cyclosporine nephrotoxicity in the rat. In humans, MMF reduced proteinuria in steroid-resistant nephrotic syndrome and had beneficial effects in the prevention and treatment of chronic allograft nephropathy and calcineurin inhibitor toxicity through the reduction of immune- and non-immune-mediated renal damage. MMF is well tolerated and has proven to be a relatively safe drug. Taken together, there is a growing body of evidence pointing to therapeutic applications of MMF other than immunosuppression, in particular the prevention of fibrosis.

Animals↗
PubMed2006

Spectroscopic characterization of copper(II) binding to the immunosuppressive drug mycophenolic acid.

Mycophenolic acid (MPA) is a drug that has found widespread use as an immunosuppressive agent which limits rejection of transplanted organs. Optimal use of this drug is hampered by gastrointestinal side effects which can range in severity. One mechanism by which MPA causes gastropathy may involve a direct interaction between the drug and gastric phospholipids. To combat this interaction we have investigated the potential of MPA to coordinate Cu(II), a metal which has been used to inhibit gastropathy associated with use of the NSAID indomethacin. Using a range of spectroscopic techniques we show that Cu(II) is coordinated to two MPA molecules via carboxylates and, at low pH, water ligands. The copper complex formed is stable in solution as assessed by mass spectrometry and 1H NMR diffusion experiments. Competition studies with glycine and albumin indicate that the copper-MPA complex will release Cu(II) to amino acids and proteins thereby allowing free MPA to be transported to its site of action. Transfer to serum albumin proceeds via a Cu(MPA)(albumin) ternary complex. These results raise the possibility that copper complexes of MPA may be useful in a therapeutic situation.

Copper↗
PubMed2005

Morphological findings in lymphatic tissues of sheep following oral application of the immunosuppressive mycotoxin mycophenolic acid.

Mycophenolic acid (MPA) is applied in immunosuppressive therapy after organ transplantation. As a common contaminant in silage, this substance is also frequently fed to sheep unintentionally. In this study, the effect of MPA on the immune system of sheep was examined. Four groups of 9 sheep each were fed 0, 0.5, 1.2, or 5 mg of MPA per kg body weight per day for 6 weeks. Then, the animals were slaughtered and various organs were examined macroscopically, histologically, and immunohistochemically. No effect of MPA on general health was detected. With increasing dose of MPA, germinal centres in the retropharyngeal lymph nodes displayed an activated morphology with numerous centroblasts. In the highest dose group, the sheep showed shrinkage of thymic lobules. The numbers of IgG or IgM positive plasma cells decreased in the ileum with increasing MPA-doses. These results suggest, that MPA in a high concentration may affect the morphology of immune organs of sheep.

Administration, Oral↗
PubMed1975

Treatment of psoriasis with oral mycophenolic acid.

Mycophenolic acid (MPA), an inhibitor of purine synthesis, was evaluated for its therapeutic and adverse effects in 29 patients with psoriasis. MPA was administered orally for at least 12 weeks, during which time the daily dose was increased from 1600 to 4800 mg depending on occurrence of adverse reactions. Complete clearing occurred in 1 of the patients, almost complete clearing in 14, definite improvement in 13, slight or doubtful improvement in 1. The full effect of MPA required a median time of 8 weeks (range 5-14). After discontinuing MPA, relapses began at a median time of 4 weeks (range 3-8). The severity of psoriasis was scored on a 0 to 108 scale using a newly devised system. The mean severity and range before treatment was 47 (21-88); after 12 weeks, 15 (0-50). Adjustment of dose on the basis of side effects resulted in a median daily dose of 3600 mg (range 2400-4800 mg; 30-96 mg/kg ideal weight). Characteristic dose-limiting side effects were soft or frequent bowel movements, diarrhea, nausea, and anorexia. One instance of reversible, dose-related leukopenia was identified.

Administration, Oral↗