title: Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure.
abstract: BACKGROUND
  Mycophenolate mofetil (MMF) acts as a prodrug for the immunosuppressive drug mycophenolic acid (MPA). It is rapidly converted to MPA following oral ingestion. MPA is metabolized to MPA glucuronide (MPAG), which is renally excreted. This study examines the pharmacokinetics of MPA and MPAG in patients with end-stage renal failure who were on hemodialysis (N = 10) or peritoneal dialysis (N = 10) treatment.
  
  
  METHODS
  After an overnight fast, a single oral dose of 1 g MMF was given. Plasma concentrations of MPA and MPAG were measured from 0 (predose) to 36 hours after administration, using high-performance liquid chromatography (HPLC). The area under the concentration time curve (AUC) from 0 to 36 hours was calculated using the trapezoidal rule.
  
  
  RESULTS
  Mean (+/- SD) AUC for MPA was 55.7 +/- 32.6 mg/L.h for hemodialysis patients and 44.7 +/- 14.7 mg/L.h for peritoneal dialysis patients, which is similar to expected values for subjects with normal renal function. The mean (+/- SD) maximum plasma concentration (Cmax) for MPA was lower than would be expected for subjects with normal renal function (16.01 +/- 10.61 mg/L for hemodialysis, 11.48 +/- 4.98 mg/L for peritoneal dialysis). MPAG clearance was prolonged with AUC approximately five times what would be expected in subjects with normal renal function (1565 +/- 596 mg/L.h for hemodialysis, 1386 +/- 410 mg/L.h for peritoneal dialysis). There was no significant difference for any of the pharmacokinetic parameters between subjects on hemodialysis and those on peritoneal dialysis. Plasma concentrations of MPA and MPAG did not fall significantly during hemodialysis. No MPA was detectable in hemodialysis or peritoneal dialysis fluid, but small amounts of MPAG were detected in hemodialysis fluid in 1 out of 10 subjects and in peritoneal dialysis fluid in 3 out of 10 subjects.
  
  
  CONCLUSIONS
  The accumulation of MPAG may be responsible for the poor gastrointestinal tolerance of this drug in dialysis patients and probably limits the maximum dose of MMF that can be tolerated.
authors.affiliation: Department of Renal Medicine and Transplantation, St. George's Hospital, London, United Kingdom. imacphee@sghms.ac.uk
authors.forename: I A
authors.initials: IA
authors.lastname: MacPhee
authors.forename: S
authors.initials: S
authors.lastname: Spreafico
authors.forename: M
authors.initials: M
authors.lastname: Bewick
authors.forename: C
authors.initials: C
authors.lastname: Davis
authors.forename: J B
authors.initials: JB
authors.lastname: Eastwood
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.forename: T
authors.initials: T
authors.lastname: Lee
authors.forename: D W
authors.initials: DW
authors.lastname: Holt
mesh_terms: D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D015314:Dialysis Solutions / Q000737:chemistry; D005260:Female; D005965:Glucuronates / Q000032:analysis / Q000097:blood; D020719:Glucuronides; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D010530:Peritoneal Dialysis; D010531:Peritoneal Dialysis, Continuous Ambulatory; D006435:Renal Dialysis
chemical_list: D015314:Dialysis Solutions; D005965:Glucuronates; D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid