Evidence map›Paper›PMID 40506684›Full record

Observational studyEuropean journal of drug metabolism and pharmacokinetics2025

Dose, Kidney Function, and a Drug-Excipient Interaction Impair Mycophenolate Mofetil Prodrug Activation in Kidney Transplant Recipients.

Fleur B Nijdam, Marieke A J Hof, Daan Kremer, Tim J Knobbe, Gérard Hopfgartner, Stephan J L Bakker, Eelko Hak, Frank Klont, TransplantLines Investigators

2 registry-linked trialsAbstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in European journal of drug metabolism and pharmacokinetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02811835 active not recruitingnot on this map

Renal Sensing of the Acidifying Effect of Sulphur-containing Amino Acids: Consequences for the Relation Between Protein Intake and Blood Pressure in Renal Transplant Recipients

Typeobservational_patient_registrySponsorUniversity Medical Center GroningenRan2008 to 2028Enrolled1,007ConditionsTransplantation Infection, Renal Transplant Donor of Left Kidney
NCT03272841 unknown statusnot on this map

TransplantLines: the Transplantation Biobank

Typeobservational_patient_registrySponsorUniversity Medical Center GroningenRan2015 to 2021Enrolled3,000ConditionsSolid Organ Tranplant Recipients, 18+ Years
3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Fleur B NijdamUnit of PharmacoTherapy, -Epidemiology, and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.ORCID https://orcid.org/0000-0003-1370-0041
Marieke A J HofDepartment of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.ORCID https://orcid.org/0000-0002-5769-1522
Daan KremerDivision of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.ORCID https://orcid.org/0000-0003-0011-115X
Tim J KnobbeDivision of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.ORCID https://orcid.org/0000-0003-3246-3192
Gérard HopfgartnerLife Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest Ansermet 24, 1211, Geneva, Switzerland.ORCID https://orcid.org/0000-0002-9087-606X
Stephan J L BakkerDivision of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.ORCID https://orcid.org/0000-0003-3356-6791
Eelko HakUnit of PharmacoTherapy, -Epidemiology, and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Frank KlontUnit of PharmacoTherapy, -Epidemiology, and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. frank.klont@rug.nl.ORCID http://orcid.org/0000-0003-3503-1694
TransplantLines Investigators

Funding

Stichting voor de Technische Wetenschappen 19060
6 · The paper itself

Abstract

BACKGROUND AND

objectiveCurrent immunosuppressive treatment to prevent graft rejection in organ transplant recipients commonly includes mycophenolate mofetil (MMF) and a calcineurin inhibitor. After absorption, MMF is activated to mycophenolate (MPA) by the carboxylesterase (CES) enzymes, which is considered to occur rapidly and completely. Recent research utilizing pharmacometabolomics (PMx), however, identified an unknown/unreported MMF glucuronide metabolite in several kidney transplant recipients (KTR). This finding indicates incomplete MMF prodrug activation by CES, thereby suggesting enzyme saturation and/or inhibition, which warrants further study. In this work, we aimed to identify clinical factors that could (partially) explain incomplete MMF activation as observed in KTR.

methodsWe analyzed untargeted urinary PMx data to determine MMF prodrug activation in 321 KTR from the TransplantLines Biobank and Cohort Study (NCT03272841) and 403 KTR from the TransplantLines Food and Nutrition Biobank and Cohort Study (NCT02811835). Beta regression was used to associate incomplete MMF activation with clinical parameters. Subsequently, in vitro experiments using human S9 liver extracts were performed to compare the influence of potential CES inhibitors on MMF activation.

resultsBeta regression linked an impaired MMF activation with increasing MMF dose and kidney function as well as with cyclosporine (CsA) use. Regarding the latter, in vitro experiments revealed a decreased MMF activation caused by the pharmaceutical excipient Kolliphor

conclusionSubstantially reduced MMF prodrug activation was observed in large numbers of KTR, indicating relevant attenuation of the MMF-converting CES enzymes, which may be due to enzyme saturation and inhibition. However, there may be other factors affecting MMF activation, which require elucidation to improve immunosuppression therapy.

Indexed as

Immunosuppressive AgentsKidney TransplantationMycophenolic AcidProdrugsAdultAgedCohort StudiesDose-Response Relationship, DrugDrug InteractionsFemaleGraft RejectionHumansKidneyMaleMiddle AgedTransplant RecipientsImmunosuppressive AgentsMycophenolic AcidProdrugs

Identifiers

PMID40506684
PMCPMC12227376

What Socratic holds

Textmetadata
LicenceCC BY-NC
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.