title: UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients.
abstract: Mycophenolate mofetil (MMF) is an immunosuppressive drug commonly used in the context of kidney transplantation. Exposure to the active metabolite mycophenolic acid (MPA) is associated with risk of allograft rejection. MPA pharmacokinetics varies between individuals, the potential cause being the presence of genetic polymorphisms in key enzymes. We genotyped 338 kidney transplant patients for UGT1A8, UGT1A9, UGT2B7, and MRP2 polymorphisms and recorded MPA exposure and biopsy-proven acute rejections (BPARs) during a 1-year follow-up. Tacrolimus-treated patients who were UGT1A9 -275T>A and/or -2152C>T carriers displayed a 20% lower MPA area under the concentration-time curve from 0 to 12 h (AUC(0-12)) (P = 0.012). UGT1A9*3 carriers displayed a 49% higher MPA AUC(0-12) when treated with tacrolimus and a 54% higher MPA AUC(0-12) when treated with cyclosporine (P < 0.005). Cyclosporine-treated UGT1A8*2/*2 (518GG) patients had an 18% higher MPA AUC(0-12) compared with noncarriers. Carrying the UGT1A9 -275T>A and/or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) MMF-treated patients receiving tacrolimus (odds ratio 13.3, 95% confidence interval 1.1-162.3; P < 0.05). UGT1A9 -275T>A and/or -2152C>T genotyping may identify patients at risk of MPA underexposure and acute rejection when receiving treatment with MMF and tacrolimus.
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, The Netherlands. r.vanschaik@erasmusmc.nl
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: M
authors.initials: M
authors.lastname: van Agteren
authors.forename: J W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.forename: J
authors.initials: J
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: D
authors.initials: D
authors.lastname: Kuypers
authors.forename: Y
authors.initials: Y
authors.lastname: Le Meur
authors.forename: M
authors.initials: M
authors.lastname: van der Werf
authors.forename: R
authors.initials: R
authors.lastname: Mamelok
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D065095:Calcineurin Inhibitors; D003404:Creatinine / Q000097:blood; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012727:Sex Characteristics; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D065095:Calcineurin Inhibitors; D003404:Creatinine; D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D016559:Tacrolimus; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human