UGT1A1 Haplotypes Associated with Reduced Glucuronidation and Increased Serum Bilirubin in Irinotecan‐administered Japanese Patients with Cancer

Purpose A comprehensive haplotype analysis of UGT1A1 in the Japanese population was conducted, and the effects of these haplotypes were investigated with respect to UGT1A1‐related phenotypic parameters in patients with cancer who received irinotecan. Methods The UGT1A1 gene, including the enhancer, the promoter, and all 5 exons and their flanking regions, was sequenced from 195 Japanese subjects. The gene was divided into 2 blocks, and the haplotypes of each block were assigned. The association of these haplotypes with area under the concentration‐time curve (AUC) ratios (7‐ethyl‐10‐hydroxycamptothecin glucuronide [SN‐38G]/7‐ethyl‐10‐hydroxycamptothecin [SN‐38]) and pretreatment levels of serum total bilirubin was investigated in 85 cancer patients who received irinotecan. Results Four haplotype groups (*1, *60, *28, and *6) were assigned in block 1, and 2 haplotype groups (*IA and *IB) were in block 2. The majority of the *IB haplotypes in block 2 were linked to either the *1 or the *60 haplotype but not to *28 in block 1. Highly significant associations were obtained between the *28 haplotypes and both a reduced AUC ratio (P = .0014, Jonckheere‐Terpstra [JT] test) and an increased total bilirubin level (P = .0007, JT test). Increased total bilirubin levels in the *60 (P = .0048, JT test) and *IB groups (P = .0224, JT test) were also observed. The reduction in the AUC ratio by the *6 group was moderate (P = .0372, JT test) but was remarkable in combination with *60 (*6/*60) or *28 (*6/*28) as compared with the *1 group (*1/*1) (P = .049 and P = .0071, respectively; nonparametric Dunnett test). Conclusion This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan. Clinical Pharmacology & Therapeutics (2004) 75, 501–515; doi: 10.1016/j.clpt.2004.01.010