Pharmacokinetics of Mycophenolic Acid and its Glucuronidated Metabolites in Stable Islet Transplant Recipients

摘要

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 mycophe-nolate 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 noncompart-mental 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 mugh/mL; dose-normalized AUC 52.9 +- 25.4 jxg h/mL/g; maximal concentration (C_(max)) 13.0 +- 6.2 |xg/mL; time to C_(max) (t_(max)) 1.2 +- 0.4 hours; minimum concentration (C_(min)) 1.4 +- 1.0 jjLg/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.