TY - JOUR T1 - Close Association of <em>UGT1A9</em> IVS1+399C&gt;T with <em>UGT1A1</em>*<em>28</em>, *<em>6</em>, or *<em>60</em> Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 272 LP - 276 DO - 10.1124/dmd.108.024208 VL - 37 IS - 2 AU - Yoshiro Saito AU - Kimie Sai AU - Keiko Maekawa AU - Nahoko Kaniwa AU - Kuniaki Shirao AU - Tetsuya Hamaguchi AU - Noboru Yamamoto AU - Hideo Kunitoh AU - Yuichiro Ohe AU - Yasuhide Yamada AU - Tomohide Tamura AU - Teruhiko Yoshida AU - Hironobu Minami AU - Atsushi Ohtsu AU - Yasuhiro Matsumura AU - Nagahiro Saijo AU - Jun-ichi Sawada Y1 - 2009/02/01 UR - http://dmd.aspetjournals.org/content/37/2/272.abstract N2 - The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C&gt;T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus, we evaluated the role of I399C&gt;T in SN-38 glucuronidation using 177 Japanese cancer patients administered irinotecan. I399C&gt;T was detected at a 0.636 allele frequency. This polymorphism was in strong linkage disequilibrium (LD) with UGT1A9*1b (–126_–118T9&gt;T10, |D′| = 0.99) and UGT1A1*6 (211G&gt;A, 0.86), in moderate LD with UGT1A1*60 (–3279T&gt;G, 0.55), but weakly associated with UGT1A1*28 (–54_–39A(TA)6TAA&gt;A(TA)7TAA, 0.25). Haplotype analysis showed that 98% of the I399C alleles were linked with low-activity haplotypes, either UGT1A1*6, *28, or *60. On the other hand, 85% of the T alleles were linked with the UGT1A1 wild-type haplotype *1. Although I399T-dependent increases in SN-38 glucuronide/SN-38 area under concentration-time curve (AUC) ratio (an in vivo marker for UGT1A activity) and decreases in SN-38 AUC/dose were apparent (P &lt; 0.0001), these effects were no longer observed after stratified patients by UGT1A1*6, *28, or *60 haplotype. Thus, at least in Japanese populations, influence of I399C&gt;T on SN-38 glucuronidation is attributable to its close association with either UGT1A1*6, *28, or *60. The American Society for Pharmacology and Experimental Therapeutics ER -