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Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients.
J Pharmacokinet Pharmacodyn. 2009 Dec; 36(6):541-64.JP

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.

Authors+Show Affiliations

Department of Hospital Pharmacy, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19904584

Citation

de Winter, Brenda C M., et al. "Pharmacokinetic Role of Protein Binding of Mycophenolic Acid and Its Glucuronide Metabolite in Renal Transplant Recipients." Journal of Pharmacokinetics and Pharmacodynamics, vol. 36, no. 6, 2009, pp. 541-64.
de Winter BC, van Gelder T, Sombogaard F, et al. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn. 2009;36(6):541-64.
de Winter, B. C., van Gelder, T., Sombogaard, F., Shaw, L. M., van Hest, R. M., & Mathot, R. A. (2009). Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. Journal of Pharmacokinetics and Pharmacodynamics, 36(6), 541-64. https://doi.org/10.1007/s10928-009-9136-6
de Winter BC, et al. Pharmacokinetic Role of Protein Binding of Mycophenolic Acid and Its Glucuronide Metabolite in Renal Transplant Recipients. J Pharmacokinet Pharmacodyn. 2009;36(6):541-64. PubMed PMID: 19904584.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. AU - de Winter,Brenda C M, AU - van Gelder,Teun, AU - Sombogaard,Ferdi, AU - Shaw,Leslie M, AU - van Hest,Reinier M, AU - Mathot,Ron A A, Y1 - 2009/11/11/ PY - 2009/07/01/received PY - 2009/10/25/accepted PY - 2009/11/12/entrez PY - 2009/11/12/pubmed PY - 2010/3/26/medline SP - 541 EP - 64 JF - Journal of pharmacokinetics and pharmacodynamics JO - J Pharmacokinet Pharmacodyn VL - 36 IS - 6 N2 - 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. SN - 1573-8744 UR - https://www.unboundmedicine.com/medline/citation/19904584/Pharmacokinetic_role_of_protein_binding_of_mycophenolic_acid_and_its_glucuronide_metabolite_in_renal_transplant_recipients_ L2 - https://doi.org/10.1007/s10928-009-9136-6 DB - PRIME DP - Unbound Medicine ER -