Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)₇TAA (UGT1A1*28), UGT1A9 766G>A (D256N; UGT1A9*5), and UGT1A9 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (± SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 ± 6466 ng·h/mL and 629 ± 370 ng·h/mL, respectively, which is in line with earlier findings. For UGT1A9*5, no variant alleles were observed, whereas for UGT1A9*3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1*28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p = .022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics.