title: Pharmacokinetics and protein adduct formation of the pharmacologically active acyl glucuronide metabolite of mycophenolic acid in pediatric renal transplant recipients.
abstract: The acyl glucuronide metabolite (AcMPAG) of mycophenolic acid (MPA) has been found to possess both immunosuppressive and pro-inflammatory activity in vitro. In this study its pharmacokinetics were determined in pediatric renal transplant recipients receiving cyclosporine, steroids, and mycophenolate mofetil. Twelve-hour concentration-time profiles for AcMPAG, MPA, and the phenolic glucuronide (MPAG) were determined by high-performance liquid chromatography (HPLC) in the initial (1-3 wk; n = 16) and stable (3-12 mo; n = 22) phases after transplantation. In addition, the formation of covalent adducts between AcMPAG and plasma albumin (AcMPAG-Alb) was investigated using Western Blot analysis. AcMPAG-AUC(12h) showed significant (p < 0.05) correlations with MPA-AUC(12h) (r = 0.78) and MPAG-AUC(12h) (r = 0.78). In molar equivalents the median AcMPAG-AUC(12h) was 10.3% (range, 4.6%-45.5%) of MPA-AUC(12h). Values (median [range]) of AcMPAG-AUC(12h) (10.1 [3.30-30.1] mg.h/L), AcMPAG-C(0) (0.48 [0.08-1.43] mg/L), and AcMPAG-C(max) (1.95 [0.88-5.35] mg/L) were significantly (p < 0.05) higher in the stable phase than in the initial phase: 3.54 [2.07-20.0] mg.h/L for AUC(12h); 0.25 [<0.04-0.97] mg/L for C(0), and 1.12 [0.32-2.44] mg/L for C(max). The increases in the AcMPAG pharmacokinetic variables were paralleled by significant increases in the corresponding MPA variables. In addition, a strong negative correlation (r = -0.69; p < 0.05) was found between AcMPAG concentrations and the creatinine clearance. AcMPAG-Alb adducts were detected in all patient samples. They showed considerable interindividual variation and increased significantly with time from the initial phase to the stable phase. AcMPAG-Alb correlated significantly (p < 0.05) with AcMPAG-AUC(12h) (r = 0.70) and plasma albumin (r = 0.40). AcMPAG plasma concentrations are dependent on renal function, MPA disposition, and glucuronidation. The pharmacokinetics of AcMPAG is characterized by broad interindividual variation. In some patients AcMPAG may significantly contribute to the immunosuppression during mycophenolate mofetil therapy. AcMPAG-Alb adduct formation may serve as a marker for extended AcMPAG exposure. The association of AcMPAG with adverse effects must be further investigated.
authors.affiliation: Department of Clinical Chemistry, Center for Internal Medicine, Georg-August-University, Robert Koch Strasse 40, D-37075 Göttingen, Germany. maria.shipkova@med.uni-goettingen.de
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Lutz
authors.initials: L
authors.lastname: Weber
authors.forename: Paul D
authors.initials: PD
authors.lastname: Niedmann
authors.forename: Eberhard
authors.initials: E
authors.lastname: Wieland
authors.forename: Jane
authors.initials: J
authors.lastname: Haley
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D019540:Area Under Curve; D015153:Blotting, Western; D002648:Child; D002673:Child, Hospitalized; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D005965:Glucuronates; D020719:Glucuronides; D007166:Immunosuppressive Agents; D012709:Serum Albumin; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid