J Clin Pharmacol
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First published on April 22, 2009, doi:10.1177/0091270009332813

The Journal of Clinical Pharmacology 2009;49:684.

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©© 2009 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology, 10.1177/0091270009332813

Article

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

Wai-Ping Yau 1, Anantharaman Vathsala 2, Huei-Xin Lou 2, Shufeng Zhou 3, and Eli Chan 1*

1 National University of Singapore
2 Singapore General Hospital
3 RMIT University, Australia

* To whom correspondence should be addressed. E-mail: phaelic{at}nus.edu.sg.


  Abstract
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 metabo-lite EHC model with a time-varying gallbladder emptying process. Simulations were performed to assess the influence of the time of bile release after dosing (Tbile) and the gallbladder emptying interval ({tau}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 Tbile and {tau}gall influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG.
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K. Rupprecht, C. Schmidt, A. Raspe, F. Schweda, M. Shipkova, W. Fischer, M. Bucher, F. Kees, and L. Faerber
Bioavailability of Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium Is Differentially Affected by Pantoprazole in Healthy Volunteers
J. Clin. Pharmacol., October 1, 2009; 49(10): 1196 - 1201.
[Abstract] [Full Text] [PDF]


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