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

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 [−57 T > 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.