Purpose: Irinotecan is metabolized to its active metabolite SN-38, which is further conjugated predominantly by UDP-glucuronosyltransferase (UGT) 1A1. In vitro studies have revealed that UGT1A7 and UGT1A9, in addition to UGT1A1, were also responsible for the metabolism of SN-38 to yield SN-38 glucuronide (SN-38G). In the present study, the phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms related to lower catalytic or transcriptional activity on the in vivo pharmacokinetics (PK) of irinotecan were examined. Methods: Sixty-five Japanese cancer patients who received various regimens of irinotecan-containing chemotherapy were enrolled. Genetic polymorphisms present in UGT1A7 (T to G transversion at -57 and UGT1A7*3) and UGT1A9 (9 repeat of T at -118) as well as UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) were analyzed for all patients. Haplotype analysis was performed with an expectation-maximization-based program using SNPAlyze 5.0 (Dynacom, Yokohama, Japan). Irinotecan PK was examined with 34 patients. Results: The most frequent haplotype (55.6%, 95%CI 51.2 to 60.0) consisted of polymorphisms related to normal catalytic or transcriptional activity, T allele at -57 of UGT1A7, UGT1A7*1, 10 repeat of T allele at -118 of UGT1A9 and UGT1A1*1. The second frequent haplotype consisted of those related to lower catalytic or transcriptional activity in which G allele at -57 of UGT1A7, UGT1A7*3 and 9 repeat of T allele at -118 of UGT1A9 linked to UGT1A1*6 (14.5%, 95%CI 11.0 to 17.9) (haplotype 2). The PK analyses revealed that seven of patients showed the apparently lower glucuronidase activity than the others, as judged by AUC ratios of SN-38 to SN-38G higher than the mean value plus 1 standard deviation (SD) (0.61+0.4). Among them, 2 patients were homozygous for the haplotype 2 related to the low catalytic and transcriptional activities of UGTs. They did not have UGT1A1*28. Another patient was heterozugous for the haplotype 2 and the opposite allele contained UGT1A1*28, although UGT1A7 and UGT1A9 were normal. These configurations of diplotypes were not found in other patients showing the AUC ratios lower than the mean value plus 1 SD. These results indicate that the homozygous combination of the haplotype 2 and its combination with UGT1A1*28 allele may be important to predict lower SN-38 glucuronidation capacity in Japanese cancer patients. Conclusion: Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 related to low catalytic and transcriptional activities of UGTs is associated with the irinotecan PK with the lower glucuronidase activity for SN-38.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]