Cancer Chemother Pharmacol (2007) 60:515–522 DOI 10.1007/s00280-006-0396-1 123 ORIGINAL ARTICLE Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer Ken-ichi Fujita · Yuichi Ando · Fumio Nagashima · Wataru Yamamoto · Hisashi Eodo · Kazuhiro Araki · Keiji Kodama · Toshimichi Miya · Masaru Narabayashi · Yasutsuna Sasaki Received: 18 August 2006 / Accepted: 12 November 2006 / Published online: 4 April 2007  Springer-Verlag 2007 Abstract Purpose The phenotypic eVects 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 irino- tecan 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 signiWcantly 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. Keywords Irinotecan · SN-38 · Polymorphism · UGT1A7 · UGT1A9 · UGT1A1*6 Introduction Irinotecan is a camptothecin analogue with high-antitumor eYcacy that acts by inhibiting topoisomerase I. Irinotecan is a prodrug metabolized to its active metabolite SN-38, which is further conjugated by hepatic UDP-glucuronosyl- transferase (UGT) 1A1, to yield the more polar, inactive SN-38 glucuronide (SN-38G) [1]. A (TA)7 within the pro- moter of the human UGT1A1 gene (UGT1A1*28) has been associated with reduced glucuronidation capacity as well as with irinotecan-related dose-limiting toxicity, most com- monly diarrhea and neutropenia [2–4]. Although UGT1A7 and UGT1A9 also participate in the glucuronidation of SN-38 in vitro [5–7], the in vivo roles of these UGTs remain poorly understood as compared with that of UGT1A1. UGT1A7 and UGT1A9, as well as UGT1A1 are encoded by a single UGT1A gene located on chromosome 2q37. UGT1A7 is expressed exclusively in the oropharynx, esophagus, stomach, and pancreas [8–12], but is absent in the liver [13]. In contrast, UGT1A9 is expressed in the liver, kidney, small intestine, colon, and reproductive organs such as the testis and ovary [8–10]. Functionally signiWcant genetic polymorphisms have been described for UGT1A7 and UGT1A9 [6, 14, 15]. UGT1A7*3, *4, *5, *8, and *9 and UGT1A9*3 and *5 K.-i. Fujita · Y. Ando · F. Nagashima · W. Yamamoto · H. Eodo · K. Araki · K. Kodama · T. Miya · M. Narabayashi · Y. Sasaki (&) Department of Clinical Oncology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan e-mail: ysasaki@saitama-med.ac.jp K.-i. Fujita Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241, Japan