Mechanism-Based Enterohepatic Circulation Model of Mycophenolic Acid and Its Glucuronide Metabolite: Assessment of Impact of Cyclosporine Dose in Asian Renal Transplant Patients
Yau, Wai-Ping Vathsala, Anantharaman Lou, Huei-Xin Zhou, Shufeng Chan, Eli
Lou, Huei-Xin
Zhou, Shufeng
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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), theMPA 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 (τ 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 bjle and τ gall influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG. © 2009 the American College of Clinical Pharmacology.
Keywords
Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, Mycophenolic acid, pharmacokinetic modeling, enterohepatic circulation, renal transplant, cyclosporine, POPULATION PHARMACOKINETIC ANALYSIS, RESISTANCE-ASSOCIATED PROTEIN-2, RANDOMIZED-TRIAL, ACUTE REJECTION, MOFETIL, RECIPIENTS, TACROLIMUS, PREVENTION, KIDNEY, COMBINATION
Source Title
JOURNAL OF CLINICAL PHARMACOLOGY
Publisher
WILEY
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Date
2009-06-01
DOI
10.1177/0091270009332813
Type
Article