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

• Published in: The Journal of clinical investigation 1998-02, Vol.101 (4), p.847-854
• Main Authors: Iyer, L, King, C D, Whitington, P F, Green, M D, Roy, S K, Tephly, T R, Coffman, B L, Ratain, M J
• Format: Article
• Language: English
• Subjects: 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; Isoenzymes - genetics; Isoenzymes - metabolism; Microsomes, Liver - metabolism; Nitrophenols - metabolism; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Uridine Diphosphate; Zidovudine - metabolism
• ISSN: 0021-9738
• 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.