Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation

Glander, Petra; Hambach, Pia; Braun, K.-P.; Fritsche, Lutz; Giessing, Markus; Mai, I.; Einecke, G.; Waiser, Johannes; Neumayer, Hans‐Hellmut; Budde, Klemens

doi:10.1111/j.1600-6143.2004.00617.x

Cited by 134 publications

(127 citation statements)

References 27 publications

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“…Intensified dosing resulted in stronger inhibition of IMPDH activity in the first week, which could be an important determinant of outcome (27,28). Although there was a statistically significant difference in IMPDH-AEC between days 3 and 10, the EC 50 values remained stable and A max was comparable to baseline pretransplantation IMPDH activity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Glander¹,

Sommerer²,

Arns³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.Design, setting, participants, & measurements: De novo kidney transplant recipients (n ‫؍‬ 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n ‫؍‬ 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n ‫؍‬ 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Glander¹,

Sommerer²,

Arns³

et al. 2010

Clinical Journal of the American Society of Nephrology

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“…Similarly, some patients show more adverse effects than do others, and hence require dose reductions more frequently. 9,15 Methods to predict individual MPA drug responsiveness or dose levels necessary for an adequate response are yet to be established. Drug monitoring was never correlated with a lower incidence of therapy failure with mycophenolate mofetil, which was confirmed in a recent study.…”

Section: Discussionmentioning

confidence: 99%

“…Differences in the MPA area under the plasma concentration time curve in transplant recipients receiving the same standard dose of mycophenolate mofetil were reported to be up to 10-fold, and in baseline IMPDH activity among patients with end-stage renal disease, this difference was over eightfold. 9,10 The substantial variability of basal IMPDH activity and MPA effectiveness might be explained by variations within IMPDH genes or in gene expression. 5 Thus, this study was conducted to elucidate a possible role of frequent variants in the IMPDH2 gene in different responsiveness to MPA by testing their functional relevance in vitro in a lymphocyte proliferation assay, as well as measuring IMPDH activity in lymphocyte-enriched peripheral blood mononuclear cells.…”

Section: Introductionmentioning

confidence: 99%

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

et al. 2009

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Mycophenolic acid (MPA) is a selective inhibitor of inosine 5 0 -monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mmol l -1 ) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mmol l -1 and 25 mmol l -1 . We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.

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“…PD monitoring of MMF, by measuring IMPDH activity, has been previously performed in kidney transplant patients (9). The effect of MMF on T cell function has been assessed both in vitro (8) (10) and in vivo in a rat heart-transplant model (11)(12)(13).…”

mentioning

confidence: 99%

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

Kamar

Glander

Nolting

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: The effect of mycophenolate mofetil (MMF) on T cell function has not been evaluated in patients undergoing kidney transplantation. The aim of this study was to assess the effect of 1g of MMF on T cell function, that is, intralymphocyte cytokine expression, T cell activation (CD25 and CD71), and T cell proliferation, as well as inosine monophosphate dehydrogenase (IMPDH) activity, to better understand the relationship between pharmacokinetic and pharmacodynamic markers in patients receiving the first dose of MMF before kidney transplantation.Patients: Twenty-four patients undergoing a kidney transplantation from a living donor were enrolled in this study. Results: Compared with baseline (before MMF intake), T cell proliferation (93%), IMPDH activity (74%), CD25 (46%), and CD71 (50%) expression significantly decreased during the first hour after MMF intake, in parallel to the rise in MPA concentration. Thereafter, all pharmacodynamic markers, except IMPDH activity, returned back to baseline level. There was a complex inverse relationship between pharmacokinetic and pharmacodynamic markers. The inhibition of T cell proliferation was highly correlated to IMPDH activity, but also to T cell activation markers.Conclusion: The administration of MMF to patients is associated not only with a dramatic decrease in both T cell proliferation and IMPDH activity, but also with in a decrease in CD25 and CD71 expression.

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Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation

Abstract: Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is

Cited by 134 publications

References 27 publications

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

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