title: UGT1A6 polymorphism and salicylic acid glucuronidation following aspirin.
abstract: OBJECTIVE
  In vivo, aspirin (acetylsalicylic acid) is rapidly deacetylated to form salicylic acid, which then undergoes primary or secondary glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs). The variant UGT1A6*2 (T181A, R184S) is associated with altered enzyme function. Our objective was to compare salicylic acid glucuronidation in individuals with different UGT1A6 genotypes.
  
  
  METHODS
  Following orally dosing with 650 mg aspirin, saliva and urine samples were collected over a period of 24 h from healthy individuals with homozygous wild-type UGT1A6 *1/*1 (n=19) and homozygous variant UGT1A6 *2/*2 (T181A, R184S) (n=9) genotypes.
  
  
  RESULTS
  No statistically significant differences were observed in salivary pharmacokinetic parameters. Urinary excretion of the sum of aspirin and its metabolites (salicyluric acid, salicyluric acid phenolic glucuronide, salicyl phenolic glucuronide, salicyl acyl glucuronide, salicylic acid) during the early period of 2-4 h of collection was significantly lower in UGT1A6 *1/*1 than in UGT1A6 *2/*2 individuals. Further, UGT1A6 *1/*1 individuals excreted a lower percentage of aspirin and its metabolites in the first 12 h and a greater percentage after 12 h than UGT1A6 *2/*2 individuals.
  
  
  CONCLUSIONS
  The variant UGT1A6*2 or polymorphisms in other UGTs that are in linkage disequilibrium with UGT1A6*2 may confer more rapid glucuronidation of salicylic acid than the wild-type UGT1A6 *1/*1.
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Gwendolyn E
authors.initials: GE
authors.lastname: Kuehl
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: Christine F
authors.initials: CF
authors.lastname: Rimorin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schwarz
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Lampe
mesh_terms: D000328:Adult; D001241:Aspirin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000652:urine; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020156:Salicylic Acid / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D012463:Saliva / Q000737:chemistry
chemical_list: D020719:Glucuronides; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D020156:Salicylic Acid; D001241:Aspirin