title: Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Paediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rother
authors.forename: P
authors.initials: P
authors.lastname: Glander
authors.forename: E
authors.initials: E
authors.lastname: Vitt
authors.forename: D
authors.initials: D
authors.lastname: Czock
authors.forename: N
authors.initials: N
authors.lastname: von Ahsen
authors.forename: V W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: M
authors.initials: M
authors.lastname: Oellerich
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: R
authors.initials: R
authors.lastname: Feneberg
authors.forename: B
authors.initials: B
authors.lastname: Tönshoff
authors.forename: L T
authors.initials: LT
authors.lastname: Weber
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood* / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009173:Mycophenolic Acid / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid