Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes

J Clin Invest. 1998 Feb 15;101(4):847-54. doi: 10.1172/JCI915.


Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / metabolism*
  • Bilirubin / metabolism
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Causality
  • Crigler-Najjar Syndrome / metabolism
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism*
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Irinotecan
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Microsomes, Liver / metabolism*
  • Nitrophenols / metabolism
  • Oxidation-Reduction
  • Rats
  • Rats, Sprague-Dawley
  • Uridine Diphosphate*
  • Zidovudine / metabolism


  • Antineoplastic Agents, Phytogenic
  • Isoenzymes
  • Nitrophenols
  • O(6)-benzylguanine
  • Zidovudine
  • Uridine Diphosphate
  • Guanine
  • Irinotecan
  • Glucuronosyltransferase
  • Bilirubin
  • Camptothecin
  • 4-nitrophenol