Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients.
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 (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 T(bile) 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.
Yau
Wai-Ping
WP
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.
Vathsala
Anantharaman
A
Lou
Huei-Xin
HX
Zhou
Shufeng
S
Chan
Eli
E
D000328:Adult; D003198:Computer Simulation; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004764:Enterohepatic Circulation / Q000187:drug effects; D005260:Female; D016473:Gallbladder Emptying; D020719:Glucuronides / Q000493:pharmacokinetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D009173:Mycophenolic Acid