title: Relationship between hyperbilirubinaemia and UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism in adult HIV-infected Thai patients treated with indinavir.
abstract: OBJECTIVE
  To investigate the association between the UGT1A1*6 (G71R) and UGT1A1*28 (promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with indinavir, and characterize the inhibition of human UGTs by indinavir in vitro.
  
  
  METHODS
  Ninety-six Thai HIV patients receiving indinavir, 800 mg t.i.d. or 800 mg b.i.d. "boosted" with ritonavir (100 mg b.i.d.), had serum bilirubin levels measured to 24 weeks post-treatment and were genotyped for UGT1A1*6 and UGT1A1*28. The inhibition selectivity and kinetics of indinavir were determined using a panel of recombinant human UGTs.
  
  
  RESULTS
  UGT1A1*6 and UGT1A1*28 frequencies in the Thai patients were 10.4% and 15.6%, respectively. Total, conjugated (direct) and unconjugated (indirect) serum bilirubin concentrations increased significantly at 24 weeks of indinavir treatment for all four genotypes, with a trend towards higher levels depending on the number of UGT1A1 mutant alleles; *6/*28 > *6 > *28 > reference. The hazards ratio (HR) for serious hyperbilirubinaemia (total bilirubin > 2.5 mg/dl) at week 24 was statistically significant only in those patients carrying the UGT1A1*6 (HR 2.87) and UGT1A1*6/*28 (HR 11.42) genotypes. The Ki values for indinavir inhibition of UGT1A1 and UGT1A1*6 were 4.1 and 10.7 mumol/l respectively. However, indinavir was also shown to inhibit other human UGTs, notably UGT1A3 and UGT1A7.
  
  
  CONCLUSIONS
  In contrast to Caucasian HIV-infected patients treated with indinavir, the promoter polymorphism (UGT1A1*28) is of less significance than the coding region (UGT1A1*6) mutation as a risk factor for hyperbilirubinaemia. The Ki values determined for indinavir inhibition of UGT1A1 are consistent with an interaction in vivo, with an additive effect in patients with already impaired bilirubin glucuronidation activity.
authors.affiliation: The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Centre, Bangkok, Thailand. mark.boyd@fmc.sa.gov.au
authors.forename: Mark A
authors.initials: MA
authors.lastname: Boyd
authors.forename: Preeyaporn
authors.initials: P
authors.lastname: Srasuebkul
authors.forename: Kiat
authors.initials: K
authors.lastname: Ruxrungtham
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.forename: Verawan
authors.initials: V
authors.lastname: Uchaipichat
authors.forename: Michael
authors.initials: M
authors.lastname: Stek
authors.forename: Joep M A
authors.initials: JM
authors.lastname: Lange
authors.forename: Praphan
authors.initials: P
authors.lastname: Phanuphak
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Wandee
authors.initials: W
authors.lastname: Udomuksorn
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000097:blood; D005787:Gene Frequency; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006932:Hyperbilirubinemia / Q000201:enzymology / Q000235:genetics*; D066298:In Vitro Techniques; D019469:Indinavir / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D013785:Thailand / Q000453:epidemiology; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D019469:Indinavir; D000099148:UGT1A1 Enzyme