title: Pharmacokinetics of mycophenolic acid and its glucuronidated metabolites in stable islet transplant recipients.
abstract: Given the paucity of data on pharmacokinetics of mycophenolic acid (MPA) in islet transplant, the aim of this study was to characterize pharmacokinetic parameters of MPA and its 2 glucuronidated metabolites in stable islet transplant recipients. Sixteen subjects were entered into this open-label study after written informed consent. Upon administration of a steady-state morning mycophenolate mofetil dose, 12-hour serial concentrations of MPA and its phenolic glucuronide (MPAG) and acyl-glucuronide (AcMPAG) were measured by a validated high-performance liquid chromatography method and pharmacokinetic parameters analyzed by noncompartmental modeling. Subjects included 11 women and 5 men who had received 2.7 +/- 0.8 islet transplants. Age was 50 +/- 8 years, weight 64 +/- 11 kg, serum albumin 4.2 +/- 0.3 g/dL, and serum creatinine 1.1 +/- 0.4 mg/dL. All patients were also on tacrolimus-based steroid-free immunosuppressant regimens. Mycophenolate mofetil dosage ranged from 1 to 2 g daily (25.4 +/- 6.1 mg/kg/d). Pharmacokinetic parameters for MPA were area under the curve 42.9 +/- 21.6 microg h/mL; dose-normalized AUC 52.9 +/- 25.4 microg h/mL/g; maximal concentration (Cmax) 13.0 +/- 6.2 microg/mL; time to Cmax (tmax) 1.2 +/- 0.4 hours; minimum concentration (Cmin) 1.4 +/- 1.0 microg/mL; and MPA-free fraction 1.2% +/- 1.0%. Area under the curve ratios of MPAG/MPA and AcMPAG/MPA were 17.8 +/- 12.4 and 0.1 +/- 0.1, respectively. The wide interpatient variability in all pharmacokinetic parameters of MPA and metabolites are consistent with results from the only other published pharmacokinetic study in islet transplant recipients. A population model and a search for significant covariates may help reduce this variability. Pharmacokinetic parameters calculated in the present study, coupled with findings from the only other published MPA study in islet transplant, form a preliminary base on which to build a population model for future multicenter studies of this little-studied transplant subpopulation.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Canada.
authors.forename: Mai
authors.initials: M
authors.lastname: Al-Khatib
authors.forename: R Jean
authors.initials: RJ
authors.lastname: Shapiro
authors.forename: Nilufar
authors.initials: N
authors.lastname: Partovi
authors.forename: Lillian S L
authors.initials: LS
authors.lastname: Ting
authors.forename: Mary H H
authors.initials: MH
authors.lastname: Ensom
mesh_terms: D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D020719:Glucuronides; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid