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

Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer, Its active meta bolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucur onosyltransferases (UGTs), The major dose-limiting toxicity of irinote can therapy is diarrhea, which is believed to be secondary to the bili ary excretion of SN-38, the extent of which is determined by SN-38 glu curonidation, The purpose of this study was to identify the specific i soform of UGT involved in SN-38 glucuronidation, In vitro glucuronidat ion 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) wi th Crigler-Najjar type I (CN-I) syndrome, A wide intersubject variabil ity in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, in dicating the pole of UGT1 isoform in SN-38 glucuronidation. A signific ant correlation was observed between SN-38 and bilirubin glucuronidati on (r = 0.89; P = 0.001), whereas there was a poor relationship betwee n para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703), In tact SN-38 glucuronidation was observed only in HK293 cells transfecte d with the UGT1A1 isozyme, These results demonstrate that UGT1A1 is th e isoform responsible for SN-38 glucuronidation, These findings indica te a genetic predisposition to the metabolism of irinotecan, suggestin g that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.