TY - JOUR
T1 - Genetic basis for the glucuronidation of SN-38
T2 - Role of UGT*1 isoform
AU - Iyer, L.
AU - Whitington, P.
AU - Roy, S. K.
AU - Ratain, M. J.
PY - 1997/12/1
Y1 - 1997/12/1
N2 - Irinotecan is a promising antitumor agent that has been recently approved for use in patients with metastatic colorectal cancer. SN-38, the active metabolite of irinotecan (CPT-11), is glucuronidated by hepatic uridine diphosphate glucuronosyl transferases (UGTs). We have previously observed major inter-individual differences in in vitro SN-38 glucuronidation by human liver microsomes. The purpose of this study was to investigate the specific isoform of UDPGT responsible for SN-38 glucuronidation. In vitro SN-38G formation was detected using a reverse-phase HPLC assay using normal human (n=33), Crigler-Najjar Type I (CN-I) patient (n=2), normal rat (n=4) and Gunn rat (n=3) liver microsomes. Microsomes from CN-I patients and Gunn rats were used as models for a genetically deficient bilirubin UDPGT system (isoform 1). SN-38G formation was detected at a mean rate of 18 ± 10 and 30 ± 3 pmoles/min/mic. protein in normal human and normal rat liver microsomes, respectively. In contrast, no SN-38G formation was detected in Gunn rats or in CN-I patients. Microsomes from all four sources indicated the presence of intact UGT*2 activity, as revealed by glucuronidation of 3′-azido-3′-deoxythymidine (AZT), a substrate for the UGT*2 form. Oxidation of O6-benzylguanine in the respective microsomes indicated presence of intact CYP3A4 activity. The results from this study indicate the possible involvement of UGT*1 in the glucuronidation of SN-38.
AB - Irinotecan is a promising antitumor agent that has been recently approved for use in patients with metastatic colorectal cancer. SN-38, the active metabolite of irinotecan (CPT-11), is glucuronidated by hepatic uridine diphosphate glucuronosyl transferases (UGTs). We have previously observed major inter-individual differences in in vitro SN-38 glucuronidation by human liver microsomes. The purpose of this study was to investigate the specific isoform of UDPGT responsible for SN-38 glucuronidation. In vitro SN-38G formation was detected using a reverse-phase HPLC assay using normal human (n=33), Crigler-Najjar Type I (CN-I) patient (n=2), normal rat (n=4) and Gunn rat (n=3) liver microsomes. Microsomes from CN-I patients and Gunn rats were used as models for a genetically deficient bilirubin UDPGT system (isoform 1). SN-38G formation was detected at a mean rate of 18 ± 10 and 30 ± 3 pmoles/min/mic. protein in normal human and normal rat liver microsomes, respectively. In contrast, no SN-38G formation was detected in Gunn rats or in CN-I patients. Microsomes from all four sources indicated the presence of intact UGT*2 activity, as revealed by glucuronidation of 3′-azido-3′-deoxythymidine (AZT), a substrate for the UGT*2 form. Oxidation of O6-benzylguanine in the respective microsomes indicated presence of intact CYP3A4 activity. The results from this study indicate the possible involvement of UGT*1 in the glucuronidation of SN-38.
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M3 - Article
AN - SCOPUS:0001266790
SN - 0009-9236
VL - 61
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 2
ER -
