Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure

Bruce Kaplan, Scott A. Gruber, Ratnaji Nallamathou, Stephen M. Katz, Les M. Shaw

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 accumulated 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 μg x hr/ml). The total MPA AUC of 36.8 μg 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 μg 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 MF-related toxicity.

Original languageEnglish (US)
Pages (from-to)1127-1129
Number of pages3
JournalTransplantation
Volume65
Issue number8
DOIs
StatePublished - Apr 27 1998
Externally publishedYes

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Mycophenolic Acid
Leukopenia
Protein Binding
Renal Insufficiency
Pancreas
Area Under Curve
Transplant Recipients
Kidney
Inosine Monophosphate

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure. / Kaplan, Bruce; Gruber, Scott A.; Nallamathou, Ratnaji; Katz, Stephen M.; Shaw, Les M.

In: Transplantation, Vol. 65, No. 8, 27.04.1998, p. 1127-1129.

Research output: Contribution to journalArticle

Kaplan, Bruce ; Gruber, Scott A. ; Nallamathou, Ratnaji ; Katz, Stephen M. ; Shaw, Les M. / Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure. In: Transplantation. 1998 ; Vol. 65, No. 8. pp. 1127-1129.
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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 accumulated 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 μg x hr/ml). The total MPA AUC of 36.8 μg 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 μg 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 MF-related toxicity.",
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