title: AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism.
abstract: Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Madelon
authors.initials: M
authors.lastname: van Agteren
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Hans
authors.initials: H
authors.lastname: de Fijter
authors.forename: Anders
authors.initials: A
authors.lastname: Hartmann
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
authors.forename: Przemyslav
authors.initials: P
authors.lastname: Pisarski
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Marloes
authors.initials: M
authors.lastname: van der Werf
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mamelok
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D065095:Calcineurin Inhibitors; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000097:blood* / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology*; D007970:Leukopenia / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies
chemical_list: D000305:Adrenal Cortex Hormones; D065095:Calcineurin Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid