Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer

Abstract

Purpose: The phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms on the in vivo pharmacokinetics of irinotecan were examined.

Methods: Eighty-four Japanese patients with cancer who received irinotecan-based chemotherapy were enrolled. Polymorphisms present in UGT1A7 (T to G transversion at -57 and UGT1A7*2 to *9), UGT1A9 (9 or 10 repeat of T at -118 [-118(T)9 or 10] and UGT1A9*2 to *5), and UGT1A1 (UGT1A1*6, UGT1A1*27, and UGT1A1*28) were analyzed for all patients. Pharmacokinetics of irinotecan were examined in 52 patients.

Results: The most frequent haplotype (haplotype I, 56.7%, 95% CI 53.1-60.4) consisted of polymorphisms related to normal catalytic or transcriptional activity [T at -57 and *1 of UGT1A7, -118(T)10 of UGT1A9, and UGT1A1*1]. The second most frequent haplotype (haplotype II, 15.0%, 95% CI 12.4-18.3) consisted of polymorphisms related to reduced catalytic or transcriptional activity [-57T > G and *3 of UGT1A7 and -118(T)9 of UGT1A9 linked to UGT1A1*6]. The AUC(SN-38)/AUC(SN-38G) ratios in three patients homozygous for haplotype II were significantly higher than those in 20 patients with I/I diplotype (P = 0.011). Neither of these patients had UGT1A1*28.

Conclusion: Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.