Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipientsReportar como inadecuado




Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Pharmacokinetics and Pharmacodynamics

, 36:541

First Online: 11 November 2009Received: 01 July 2009Accepted: 25 October 2009

Abstract

Mycophenolic acid MPA, the active compound of mycophenolate mofetil MMF, is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation EHC. MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA tMPA, unbound MPA fMPA, total MPAG tMPAG and unbound MPAG fMPAG. In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine n = 48 and tacrolimus n = 45 were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding bMPA and bMPAG. tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment P < 0.001. In the model, clearance of fMPAG decreased when creatinine clearance CrCL was reduced P < 0.001, and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG P < 0.001. In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol-l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.

KeywordsMycophenolic acid Population pharmacokinetics Protein binding Renal transplant recipients Mechanism-based pharmacokinetic model List of symbolsMPAMycophenolic acid

MPAGMycophenolic acid glucuronide

tTotal concentration

fUnbound concentration

TLAGLag-time

kaFirst order absorption rate constant

VcCentral volume

CLClearance

VpPeripheral volume

QIntercompartmental clearance

knmRate constant between compartment n and m

BMAXMaximum number of protein binding sites

TGBTime of gallbladder emptying

DGBDuration of gallbladder emptying

IPVInterpatient variability

CrCLCreatinine clearance

CsACyclosporine

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Autor: Brenda C. M. de Winter - Teun van Gelder - Ferdi Sombogaard - Leslie M. Shaw - Reinier M. van Hest - Ron A. A. Math

Fuente: https://link.springer.com/



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