title: Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure.
abstract: BACKGROUND
  Mycophenolate mofetil (MMF) is rapidly hydrolyzed to its active metabolite mycophenolic acid (MPA), which is excreted by the kidney after undergoing glucuronidation to MPAG. MPAG has been shown to accumulate in patients with renal failure. MPA is extensively and avidly bound to human serum albumin. In vitro inhibition of the pharmacologic target, inosine monophosphate dehydrogenase, is dependent on free MPA. It has been demonstrated that high MPAG concentrations decrease MPA protein binding in vitro. In addition, the uremic state is associated with altered protein binding of many drugs.
  
  
  METHODS
  We assessed free MPA, total MPA, and MPAG kinetics in a patient with renal failure receiving MMF for a pancreas transplant, who presented with signs of MMF toxicity. MPA, MPAG, and free MPA were measured by high performance liquid chromatography and a validated 14C-MPA ultrafiltration methodology.
  
  
  RESULTS
  The MPAG area under the concentration curve (AUC) in this patient was extremely high (5899 microg x hr/ml). The total MPA AUC of 36.8 microg x hr/ml was within the range usually obtained in stable renal patients. The free fraction of MPA and the free MPA AUC were markedly elevated (13.8% and 5.07 microg x hr/ml, respectively).
  
  
  CONCLUSIONS
  Patients with severe renal insufficiency may have markedly increased free MPA levels that may not be reflected in total MPA concentrations. These patients may be at increased risk for MMF-related toxicity.
authors.affiliation: Division of Renal Disease, University of Texas at Houston, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kaplan
authors.forename: S A
authors.initials: SA
authors.lastname: Gruber
authors.forename: R
authors.initials: R
authors.lastname: Nallamathou
authors.forename: S M
authors.initials: SM
authors.lastname: Katz
authors.forename: L M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology / Q000601:surgery*; D003928:Diabetic Nephropathies / Q000097:blood / Q000150:complications; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016035:Pancreas Transplantation / Q000502:physiology*; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D005965:Glucuronates; D007166:Immunosuppressive Agents; D012709:Serum Albumin; D009173:Mycophenolic Acid