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Mechanism-Based Enterohepatic Circulation Model of Mycophenolic Acid and Its Glucuronide Metabolite: Assessment of Impact of Cyclosporine Dose in Asian Renal Transplant Patients

From the Department of Pharmacy, Faculty of Science, National University of Singapore (Dr Yau, Dr Chan); Department of Renal Medicine (Dr Vathsala) and Department of Pharmacy (Dr Lou), Singapore General Hospital, Singapore; and School of Health Sciences, RMIT University, Victoria, Australia (Dr Zhou).

Mycophenolic acid (MPA) is mainly metabolized to MPA-glucuronide (MPAG), which may be reconverted to MPA following enterohepatic circulation (EHC). A physiologically realistic EHC model was proposed to estimate and assess the impact of cyclosporine (CsA) dose on the extent of EHC of MPA and MPAG. After the first oral dose of mycophenolate mofetil (MMF), the MPA and MPAG plasma concentration-time data of 14 adult renal transplant patients (12 receiving concomitant CsA and prednisolone and 2 receiving only concomitant prednisolone without CsA) were analyzed by individual pharmacokinetic modeling using a proposed 5-compartment drug and metabolite EHC model with a time-varying gallbladder emptying process. Simulations were performed to assess the influence of the time of bile release after dosing (T_bile) and the gallbladder emptying interval (_gall) on the EHC process. The extent of EHC for both MPA and MPAG tended to be lower in the group receiving CsA coadministration and decreased with increasing total body weight-adjusted CsA dose. Simulations revealed that T_bile and _gall influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG.

Key Words: Mycophenolic acid • pharmacokinetic modeling • enterohepatic circulation • renal transplant • cyclosporine

Address for reprints: Eli Chan, PhD, Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore; e-mail: phaelic{at}nus.edu.sg.

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