, Volume 60, Issue 4, pp 515-522
Date: 04 Apr 2007

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

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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 AUCSN-38/AUCSN-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.