title: Plasma and intracellular pharmacokinetic-pharmacodynamic analysis of mycophenolic acid in de novo kidney transplant patients.
abstract: OBJECTIVE
  Little is known about the correlation between the inosine-monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation.
  
  
  METHODS
  Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T0, T1.5 and T3.5 following the morning dose, on days 2, 4 and 10 post-transplantation. All subjects were treated with a fixed MMF dose (500 mg twice-a-day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS.
  
  
  RESULTS
  Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10 days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T1.5, before returning to its pre-dose levels at T3.5. IMPDH inhibition at T1.5 better correlated with plasma MPA AUC(0-3.5) (p=0.027) than with PBMC AUC(0-3.5) (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower.
  
  
  CONCLUSIONS
  These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities.
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium.
authors.forename: Minh Thuan Nguyen
authors.initials: MT
authors.lastname: Thi
authors.affiliation: Department of Surgery, Surgery and Abdominal Transplantation Division, Cliniques Universitaires St Luc, Brussels, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Mourad
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Capron
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium.
authors.forename: Flora Musuamba
authors.initials: FM
authors.lastname: Tshinanu
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Vincent
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université catholique de Louvain, UCL, Brussels, Belgium. Electronic address: pierre.wallemacq@uclouvain.be.
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
keywords: Inosine monophosphate dehydrogenase (IMPDH); Intracellular MPA; Kidney transplantation; Mycophenolic acid; PBMC