title: Atypical pharmacokinetics and metabolism of mycophenolic acid in a young kidney transplant recipient with impaired renal function.
abstract: A juvenile, female renal transplant recipient suffered two acute rejection episodes: the first on posttransplant day 31 while taking cyclosporine, prednisone, and mycophenolate mofetil (MMF); and the second on posttransplant day 67, when she was taking tacrolimus, prednisone, and MMF. Dosage of MMF was initially started at 2 g/d (corresponding to 600 mg MMF/m(2) twice daily.), but was reduced to 250 mg/d to 500 mg/d after severe diarrhea and a paralytic ileus on posttransplant day 16. During therapy with tacrolimus, prednisone, and MMF, predose plasma mycophenolic acid (MPA) concentrations varied from 1.1 mg/L to 8.2 mg/L (median 3.0 mg/L). On posttransplant day 91, a 12-hour pharmacokinetic profile was obtained. The concentrations of MPA and its metabolites were determined with a validated high-performance liquid chromatography (HPLC) procedure. After oral MMF (250 mg) administration, the MPA concentration showed an atypical decline from a predose concentration of 6.0 mg/L to a value of 3.8 mg/L at 75 minutes postdose, and 3.4 mg/L at 6 hours postdose, before returning to 6.0 mg/L after 12 hours. The 12-hour area under the concentration-time curve (AUC) values for MPA and its major metabolite the phenolic glucuronide MPAG were 55.1 mg.h/L and 800 mg.h/L, respectively. An unusually high concentration (12-h AUC, 165 mg.h/L) of the phenolic glucose conjugate of MPA was found. The apparent renal clearance of MPAG was only 2.2 mL/min. Her creatinine clearance was 30 mL/min. MPAG clearances have been reported to range from approximately. 5.5 mL/min to 35 mL/min at a creatinine clearance of approximately 30 mL/min in renal transplant recipients. The authors' findings suggest that conjugation and clearance of MPA through the kidney is strongly impaired in this patient. The relatively high predose MPA concentrations could result from an enhanced enterohepatic circulation of MPA and its metabolites.
authors.affiliation: Department for Pediatric Nephrology and Dialysis, University of Rostock, Rostock, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Wigger
authors.forename: Victor William
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Rainer
authors.initials: R
authors.lastname: Wacke
authors.forename: Horst
authors.initials: H
authors.lastname: Nizze
authors.forename: Frank
authors.initials: F
authors.lastname: Streit
authors.forename: Nicolas
authors.initials: N
authors.lastname: von Ahsen
authors.forename: Jutta
authors.initials: J
authors.lastname: Muscheites
authors.forename: Sabine
authors.initials: S
authors.lastname: Glasenapp
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Stolpe
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid