title: UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan.
abstract: BACKGROUND
  Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1.
  
  
  METHODS
  Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients.
  
  
  RESULTS
  The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 +/- 1110 (range 840-3730) in patients with 7/7 versus 6/6 genotypes, respectively.
  
  
  CONCLUSIONS
  These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Japan. yando@tsuru.med.nagoya-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Ando
authors.forename: H
authors.initials: H
authors.lastname: Saka
authors.forename: G
authors.initials: G
authors.lastname: Asai
authors.forename: S
authors.initials: S
authors.lastname: Sugiura
authors.forename: K
authors.initials: K
authors.lastname: Shimokata
authors.forename: T
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D016385:TATA Box
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002166:Camptothecin