title: Renal graft function and low-dose cyclosporine affect mycophenolic acid pharmacokinetics in kidney transplantation.
abstract: BACKGROUND
  In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined.
  
  
  METHODS
  One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis.
  
  
  RESULTS
  Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37±27.93 μg hr/mL/g MMF) than in those with mild (stage 2: 47.46±11.66 μg hr/mL/g MMF) or moderate (stage 3; 47.48±15.22 μg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12.
  
  
  CONCLUSIONS
  In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.
authors.affiliation: Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Via G B Camozzi 3, Bergamo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cortinovis
authors.forename: Eliana
authors.initials: E
authors.lastname: Gotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Pradini
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007668:Kidney / Q000503:physiopathology; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; D011355:Prodrugs; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D009173:Mycophenolic Acid