title: UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.
abstract: BACKGROUND
  Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.
  
  
  METHODS
  MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C.
  
  
  RESULTS
  Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05).
  
  
  CONCLUSIONS
  Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA. tsuyoshi.fukuda@cchmc.org
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Jens
authors.initials: J
authors.lastname: Goebel
authors.forename: Shareen
authors.initials: S
authors.lastname: Cox
authors.forename: Denise
authors.initials: D
authors.lastname: Maseck
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Sherbotie
authors.forename: Eileen N
authors.initials: EN
authors.lastname: Ellis
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004351:Drug Resistance; D005260:Female; D056726:Genetic Association Studies; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D000090264:UDP-Glucuronosyltransferase 1A9; D014481:United States; D055815:Young Adult
chemical_list: D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D011355:Prodrugs; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human; C491474:UGT2B7 protein, human