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Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.

Methods

We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.

Results

Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.

Conclusions

In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.

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Abbreviations

A:

IMPDH activity

AEC:

Area under the enzyme activity–time curve

AIC:

Akaike information criterion

Alow :

Maximal possible IMPDH inhibition

Amin :

Minimum IMPDH activity

AMP:

Adenosine monophosphate

ANOVA:

Analysis of variance

AUC:

Area under the concentration–time curve

BSA:

Body surface area

BMI SDS:

Body mass index standard deviation score

C:

MPA concentration

CL/F:

Apparent drug clearance

Cmax :

Maximum MPA concentration

D:

Administered MPA content

ESRD:

End-stage renal disease

Freq:

Frequency

H:

Sigmoidicity parameter

HPLC:

High-performance liquid chromatography

IMPDH:

Inosine 5’-monophosphate dehydrogenase

MPA:

Mycophenolic acid

MMF:

Mycophenolate mofetil

PBMCs:

Peripheral blood mononuclear cells

PD:

Pharmacodynamic

PK:

Pharmacokinetic

RTx:

Renal transplantation

SD:

Standard deviation

SNP:

Single nucleotide polymorphism

tAmin :

Time to minimum IMPDH activity

tCmax :

Time of maximum MPA concentration in a dosing interval

XMP:

Xanthosine 5’-monophosphate

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Acknowledgements

We gratefully acknowledge the expert technical assistance of Sandra Hartung and Ulrike Hügel.

Funding source

This study was supported by the Peter-Stiftung für die Nierenwissenschaft (scientific foundation to promote kidney research, particularly in children). The manuscript was not prepared or funded by a commercial organisation.

Conflicts of interest

Lutz T. Weber and Burkhard Tönshoff have received research grants from Roche Pharma AG and Novartis Pharma GmbH. Klemens Budde has received research grants and honoraria from Roche Pharma AG and Novartis Pharma GmbH.

Author information

Authors and Affiliations

  1. Department of Paediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany

    A. Rother, R. Feneberg & B. Tönshoff

  2. Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany

    P. Glander & K. Budde

  3. Department of Paediatric Nephrology, Children’s Hospital of the Ludwig-Maximilians University of Munich, Munich, Germany

    E. Vitt & L. T. Weber

  4. Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany

    D. Czock

  5. Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany

    N. von Ahsen, V. W. Armstrong & M. Oellerich

  6. Paediatric Nephrology, University Children’s Hospital, Dr. von Haunersche Kinderklinik, Lindwurmstrasse 4, 80337, Munich, Germany

    L. T. Weber

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  1. A. Rother
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  6. V. W. Armstrong
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Corresponding author

Correspondence to L. T. Weber.

Additional information

B. Tönshoff and L. T. Weber contributed equally to this work

V. W. Armstrong: Date of death: 27 February 2010

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Rother, A., Glander, P., Vitt, E. et al. Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid. Eur J Clin Pharmacol 68, 913–922 (2012). https://doi.org/10.1007/s00228-011-1203-4

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  • DOI: https://doi.org/10.1007/s00228-011-1203-4

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