Identification of glucoside and carboxyl‐linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil

Shipkova, Maria; Armstrong, Victor W.; Wieland, Eberhard; Niedmann, Paul Dieter; Schütz, Ekkehard; Brenner‐Weiß, Gerald; Voihsel, Martin; Braun, Felix; Oellerich, Michael

doi:10.1038/sj.bjp.0702399

Cited by 194 publications

(122 citation statements)

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“…It is acknowledged that only MPAG formation has been characterized in this study, and other pathways contribute to MPA elimination. However, the alternative metabolic pathways are apparently minor compared with MPAG formation [3], and renal clearance of unchanged MPA is negligible [2].…”

Section: Discussionmentioning

confidence: 99%

“…The principal elimination mechanism of MPA is conjugation of the phenol group to form the inactive 7-hydroxy-b-glucuronide, generally referred to as mycophenolic acid glucuronide (MPAG) [1±3]. The 7-O-glucoside, acyl glucuronide and a cytochrome P450 catalysed oxidation product have recently been identi®ed as minor metabolites of MPA in humans [3]. Renal clearance of unchanged MPA is negligible [2].…”

Section: Introductionmentioning

confidence: 99%

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The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

Bowalgaha

Miners

2001

Brit J Clinical Pharma

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Aims To estimate the relative contribution of liver, kidney and jejunum to MPA elimination via glucuronidation from in vitro kinetic data. Methods The kinetics of MPA glucuronidation by human liver, kidney and jejunum microsomes were characterized. Mycophenolic acid glucuronide (MPAG) concentrations in microsomal incubations were determined using a speci®c h.p.l.c. procedure. Non-speci®c microsomal binding of MPA was excluded using an equilibrium dialysis approach. Results Microsomes from all three tissues catalysed the conversion of MPA to MPAG. Mean microsomal intrinsic clearances for MPAG formation by liver, kidney and jejunum microsomes were 46.6, 73.5 and 24.5 ml (min mg) x1 , respectively. When extrapolated to the whole organ, however, hepatic intrinsic clearance was 21-and 38-fold higher than the respective intrinsic clearances for kidney and small intestine. Conclusions The data suggest that the liver is the organ primarily responsible for the systemic clearance of MPA, with little contribution from the kidney, and that the small intestine would be expected to contribute to ®rst-pass extraction to a minor extent only.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

Bowalgaha

Miners

2001

Brit J Clinical Pharma

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“…Since curcumin reversibly inhibited glucuronidation of MPA without detectable toxicity, which is consistent with its beneficial effects that include anti-oxidant [20,21], antiinflammatory [22] and anti-carcinogenic [20,21] without detectable toxicity in mice or human, we tested its effect on free MPA levels in systemic blood [11] and immunosuppression [6] in antigen-treated mice. Oral administration of 100 mg curcumin/kg to SRBC-stimulated mice revealed a 6-and 7-fold increase in blood free MPA for 25 and 50 mg/kg, respectively; at the same time MPA glucuronide remaining in the blood was reduced by about 25 % (Fig.…”

Section: Major Improvement In Serum Free Mpa Uptake and Its Immunosupmentioning

confidence: 99%

“…Mice were sacrificed, and spleens were removed and processed for radioactivity as described under Methods. Simultaneously, blood was collected to ship for HPLC analysis [11] in order to distinguish free and MPA glucuronides. CPM/mg protein were determined and expressed as a percentage (treated/ control) shown in (B).…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…Whereas MPA readily forms ether-linked-(MPAG) or acyl-glucuronides (AcMPAG) [9][10][11], we studied MPA glucuronidation in vitro with human UGTs and found 4 isozymes are avid metabolizers [12] that reach saturation kinetics between 1.6 and 2.4 mM with Km values between 0.25 and 0.55 mM. These UGT isozymes, encoded at the UGT1 complex locus, were found strategically and differentially expressed in the gastrointestinal (GI) mucosa [1].…”

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confidence: 99%

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Targeted inhibition of glucuronidation markedly improves drug efficacy in mice—A model

Basu

Kole

Basu

et al. 2007

Biochemical and Biophysical Research Communications

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Finding UDP-glucuronosyltransferases (UGT) require protein kinase C-mediated phosphorylation is important information that allows manipulation of this critical system. UGTs glucuronidate numerous aromatic-like chemicals derived from metabolites, diet, environment and, inadvertently, therapeutics to reduce toxicities. As UGTs are inactivated by downregulating PKCs with reversiblyacting dietary curcumin, we determined the impact of gastro-intestinal glucuronidation on free-drug uptake and efficacy using immunosuppressant, mycophenolic acid (MPA), in mice. Expressed in COS-1 cells, mouse GI-distributed Ugt1a1 glucuronidates curcumin and MPA and undergoes irreversibly and reversibly dephosphorylation by PKC-specific inhibitor calphostin-C and generalkinase inhibitor curcumin, respectively, with parallel effects on activity. Moreover, oral curcuminadministration to mice reversibly inhibited glucuronidation in GI-tissues. Finally, successive oraladministration of curcumin and MPA to antigen-treated mice increased serum free-MPA and immunosuppression up to 9-fold. Results indicate targeted inhibition of GI-glucuronidation in mice markedly improved free-chemical uptake and efficacy using MPA as a model.Whereas the primary role of UDP-glucurononsyltransferases (UGT) is to detoxify numerous structurally diverse lipophilic chemicals, including metabolites, dietary constituents, environmental toxicants, carcinogens and, inadvertently, therapeutic chemicals, there is a limited capacity to manipulate glucuronidation to improve protection or reduce premature ‡ Corresponding authors at: National Institutes of Health, Building 10, Room 8D-42, Bethesda, MD 20892-1830, E-mail addresses, telephone and fax numbers: owensi@mail.nih.gov; 301-496-6091, and 301-480-8042; basun@mail.nih.gov, 301-496-8825, 301-451-4288. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Whereas MPA readily forms ether-linked-(MPAG) or acyl-glucuronides (AcMPAG) [9-11], we studied MPA glucuronidation in vitro with human UGTs and found 4 isozymes are avid metabolizers [12] that reach saturation kinetics between 1.6 and 2.4 mM with Km values between 0.25 and 0.55 mM. These UGT isozymes, encoded at the UGT1 complex locus, were found strategically and differentially expressed in the gastrointestinal (GI) mucosa [1]. In this report, we established under both in-vitro and in-vivo conditions that mouse Ugt1a1 also requires phosphorylation, which can be transiently downregulated by nontoxic kinase inhibitor, curcumin [2,3,13], and irreversibly by calphostin-C, similar to that for human UGTs [2,3]. Moreover, effects of...

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Immunosuppressive Agents for the Prevention of Transplantation Rejection

Pitts

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus), mTOR ( m ammalian t arget o f r apamycin ) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP‐690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab‐CD3, basiliximab, and daclizumab) are discussed elsewhere.

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Identification of glucoside and carboxyl‐linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil

Cited by 194 publications

References 24 publications

The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

Targeted inhibition of glucuronidation markedly improves drug efficacy in mice—A model

Immunosuppressive Agents for the Prevention of Transplantation Rejection

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