UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity

Pharmacogenomics J. 2002;2(1):43-7. doi: 10.1038/sj.tpj.6500072.


The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m(-2)) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6--45%, 6/7--35% and 7/7--20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacokinetics*
  • Camptothecin / toxicity
  • Female
  • Genotype
  • Glucuronides / pharmacokinetics
  • Glucuronosyltransferase / genetics*
  • Humans
  • Irinotecan
  • Male
  • Polymorphism, Genetic*


  • 7-ethyl-10-hydroxycamptothecin glucuronide
  • Antineoplastic Agents, Phytogenic
  • Glucuronides
  • Irinotecan
  • Glucuronosyltransferase
  • Camptothecin