Abstract
What is already known about this subject: Mycophenolic acid (MPA) undergoes enterohepatic circulation (EHC) in the body and several population models have been proposed to describe this process using sparse data. Recent studies in Whites have found that polymorphism in UGT1A9 could partly explain the large interindividual variability associated with the pharmacokinetics of MPA. What this study adds: A new population pharmacokinetic model for EHC combining MPA and its main glucuronide metabolite (MPAG) simultaneously was established based on physiological aspects of biliary excretion using intensive sampling data. Pharmacokinetic profiles of MPA and MPAG with the UGT1A9 polymorphism in healthy Chinese were characterized. AIMS To establish a population pharmacokinetic model that describes enterohepatic circulation (EHC) of mycophenolic acid (MPA) based on physiological considerations and to investigate the influence of polymorphisms of UGT1A9 on the pharmacokinetics of MPA. Methods: Pharmacokinetic data were obtained from two comparative bioavailability studies of oral mycophenolic mofetil formulations. Nonlinear mixed effects modelling was employed to develop an EHC model including both MPA and its main glucuronide metabolite (MPAG) simultaneously. Demographic characteristics and UGT1A9 polymorphisms were screened as covariates. Results: In total, 590 MPA and 589 MPAG concentration-time points from 42 healthy male volunteers were employed in this study. The chain compartment model included an intestinal compartment, a gallbladder compartment, a central and a peripheral compartment for MPA and a central compartment for MPAG. The typical population clearance (CL/F) estimates with its relative standard error for MPA and MPAG were 10.2 l h(-1) (5.7%) and 1.38 l h(-1) (6.9%), respectively. The amount of MPA recycled in the body was estimated to be 29.1% of the total amount absorbed. Covariate analysis showed that body weight was positively correlated with CL/F of MPA, intercompartment CL/F of MPA and distribution volume of MPA peripheral compartment. Polymorphisms of UGT1A9 did not show any effect on the pharmacokinetics of MPA and MPAG. The model evaluation tests indicated that the proposed model can describe the pharmacokinetic profiles of MPA and MPAG in healthy Chinese subjects. Conclusions: The proposed model may provide a valuable approach for planning future pharmacokinetic-pharmacodynamic studies and for designing proper dosage regimens of MPA.