title: Pharmacokinetic modelling of the plasma protein binding of mycophenolic acid in renal transplant recipients.
abstract: OBJECTIVE
  Renal function and the plasma albumin concentration have been shown to correlate with clearance of total mycophenolic acid (MPA). The hypothesis for the underlying mechanism is that low plasma albumin concentrations and accumulation of the glucuronide metabolite of MPA (MPAG) decrease the binding of MPA to albumin. The subsequent increase in the unbound fraction (f(u)) of MPA (MPA(u)) produces an increase in total MPA (MPA(t)) clearance. This study aimed to develop an empirical population pharmacokinetic model to describe the relationships between renal function and albumin concentration and MPAG, MPA(u) and MPA(t), in order to provide insight into the mechanism by which renal function and plasma albumin affect the disposition of MPA.
  
  
  METHODS
  774 MPA(t), 479 MPA(u) and 772 total MPAG (MPAG(t)) plasma concentrations were available from 88 renal transplant recipients on days 11 and 140 after transplantation. Data were analysed using non-linear mixed-effects modelling.
  
  
  RESULTS
  Time profiles of MPA(u) and MPAG(t) concentrations were adequately described by two 2-compartment pharmacokinetic models with a link between the central compartments, representing the glucuronidation of MPA(u) to form MPAG. MPA(t) concentrations were modelled using: [MPA(t)] = [MPA(u)] + [MPA(u)] * theta(pb), with [MPA(u)] * theta(pb) representing the bound MPA concentration, where [MPA(t)], [MPA(u)] and theta(pb) represent MPA(t) concentration, MPA(u) concentration and a factor that correlates to the total number of protein binding places, respectively. According to this equation, f(u) = [MPA(u)]/[MPA(t)] = 1/(1 + theta(pb)) * theta(pb), and therefore [MPA(t)], was significantly and independently correlated with creatinine clearance (CL(CR)), the plasma albumin concentration and the MPAG(t) concentration (all p < 0.001). A reduction in CL(CR) from 60 to 25 mL/min correlated with an increase in f(u) from 2.7% to 3.5%, accumulation of MPAG(t) concentrations from 50 to 150 mg/L correlated with an increase in f(u) from 2.8% to 3.7%, and a decrease in plasma albumin concentration from 40 to 30 g/L correlated with an increase in f(u) from 2.6% to 3.5%. No significant correlations were detected between MPA(u) clearance and the plasma albumin concentration or CL(CR).
  
  
  CONCLUSIONS
  The model shows that low CL(CR), low plasma albumin concentrations and high MPAG concentrations decrease MPA(t) exposure by affecting MPA binding to albumin.
authors.affiliation: Department of Hospital Pharmacy, Erasmus Medical Centre, 3000 CA Rotterdam, the Netherlands. r.vanhest@ahz.nl
authors.forename: Reinier M
authors.initials: RM
authors.lastname: van Hest
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
mesh_terms: D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D001798:Blood Proteins / Q000378:metabolism*; D003198:Computer Simulation; D003404:Creatinine / Q000378:metabolism; D054796:Drug Dosage Calculations; D004359:Drug Therapy, Combination; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007668:Kidney / Q000502:physiology; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D012709:Serum Albumin / Q000032:analysis; D055815:Young Adult
chemical_list: D001798:Blood Proteins; D020719:Glucuronides; D007166:Immunosuppressive Agents; D012709:Serum Albumin; D003404:Creatinine; D009173:Mycophenolic Acid
references.citation: Eur J Cancer. 2003 May;39(8):1105-14
references.pmid: 12736110
references.citation: Ther Drug Monit. 1999 Oct;21(5):498-506
references.pmid: 10519445
references.citation: Clin Pharmacol Ther. 1998 Dec;64(6):672-83
references.pmid: 9871432
references.citation: J Am Soc Nephrol. 2002 Mar;13(3):759-768
references.pmid: 11856782
references.citation: Ther Drug Monit. 2001 Apr;23(2):119-28
references.pmid: 11294511
references.citation: J Clin Pharmacol. 1998 Mar;38(3):268-75
references.pmid: 9549665
references.citation: J Chromatogr B Biomed Appl. 1996 Jan 12;675(1):119-29
references.pmid: 8634753
references.citation: Br J Clin Pharmacol. 2005 Mar;59(3):271-80
references.pmid: 15752372
references.citation: Transplantation. 1999 Jul 27;68(2):261-6
references.pmid: 10440399
references.citation: Nephron. 1976;16(1):31-41
references.pmid: 1244564
references.citation: J Pharmacokinet Biopharm. 1993 Dec;21(6):735-50
references.pmid: 8138894
references.citation: Am J Transplant. 2004;4 Suppl 9:38-53
references.pmid: 15113354
references.citation: Clin Pharmacol Ther. 2002 Mar;71(3):115-21
references.pmid: 11907485
references.citation: J Clin Pharmacol. 1999 Jul;39(7):715-20
references.pmid: 10392326
references.citation: AAPS J. 2005 Oct 07;7(3):E523-31
references.pmid: 16353930
references.citation: Am J Transplant. 2005 May;5(5):987-94
references.pmid: 15816878
references.citation: J Pharmacokinet Biopharm. 1992 Oct;20(5):511-28
references.pmid: 1287200
references.citation: Ther Drug Monit. 2004 Aug;26(4):453-5
references.pmid: 15257077
references.citation: J Pharmacokinet Pharmacodyn. 2001 Apr;28(2):109-28
references.pmid: 11381566
references.citation: Clin Chem. 1995 Jul;41(7):1011-7
references.pmid: 7600680
references.citation: Clin Pharmacokinet. 1998 Jun;34(6):429-55
references.pmid: 9646007
references.citation: Clin Pharmacol Ther. 1999 Nov;66(5):492-500
references.pmid: 10579476
references.citation: Ther Drug Monit. 2004 Jun;26(3):284-6
references.pmid: 15167629
references.citation: J Pharmacokinet Biopharm. 1983 Jun;11(3):303-19
references.pmid: 6644555
references.citation: Br J Pharmacol. 2001 Mar;132(5):1027-34
references.pmid: 11226133
references.citation: J Am Soc Nephrol. 2006 Mar;17(3):871-80
references.pmid: 16452491
references.citation: Clin Pharmacokinet. 2005;44(10):1083-96
references.pmid: 16176120
references.citation: Am J Transplant. 2004 Jul;4(7):1079-83
references.pmid: 15196064
references.citation: J Am Soc Nephrol. 1998 Aug;9(8):1511-20
references.pmid: 9697675
references.citation: Pharm Res. 1995 Dec;12(12):1845-55
references.pmid: 8786955
references.citation: Transplantation. 1998 Apr 27;65(8):1127-9
references.pmid: 9583876
references.citation: Drug Metab Dispos. 2005 Jan;33(1):139-46
references.pmid: 15470161
references.citation: Ther Drug Monit. 2003 Oct;25(5):609-22
references.pmid: 14508385
references.citation: Clin Pharmacol Ther. 1975 Oct;18(4):377-90
references.pmid: 1164821
references.citation: J Clin Pharmacol. 2000 Jun;40(6):624-33
references.pmid: 10868313