2072 Background: The uridine diphosphate-glucuronsyltransferase 1A (UGT1A) family of enzymes is involved in the phase II biotransformation of various drugs, including the irinotecan metabolite, SN-38. The isoforms 1A1 and 1A9 are responsible for most of the glucuronidation of SN-38. Several genetic variants in the UGT1A9 gene have been described recently with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A9 766G>A (D256N) and 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan given as a 90-minute i.v. infusion, as well as the UGT1A1 (TA)n polymorphism (UGT1A1*28). Methods: Pharmacokinetic studies were performed after the first course of irinotecan (median dose, 600 mg) in a cohort of 94 Caucasian patients (47 males; 47 females) with a mean age of 54 years. Plasma concentrations of irinotecan, SN-38, and SN-38-glucuronide (SN-38G) were determined using HPLC and time profiles were analyzed using NONMEM. Genotyping was performed using direct DNA sequencing. Results: In the entire population, the mean area under the plasma-concentration time curves (AUCs) of irinotecan and SN-38 were 20.3 ± 6.46 μg×h/ml and 629 ± 370 ng×h/ml, respectively, which is in line with earlier findings. For UGT1A9 766G>A, no variant alleles were observed, whereas for UGT1A9*3, the wild-type sequence was observed in all but 1 patient (allele frequency, 0.7%). The genotype distribution of the UGT1A1*28 variant showed 44 patients carrying the wild-type sequence (WT), 37 heterozygous (Het), and 5 homozygous (Var). The extent of SN-38 glucuronidation (ie, the AUC ratio of SN-38G to SN-38) was significantly reduced in carriers of the variant UGT1A1*28 allele [7.82 (WT) vs 7.74 (Het) vs 3.46 (Var); P = .022, Kruskal-Wallis test]. No significant association of UGT1A1*28 with the occurrence of diarrhea was observed. Conclusions: Functional variants in the UGT1A9gene are rare in Caucasian patients, and of unlikely clinical significance in relation to irinotecan treatment. As predicted previously, screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics. No significant financial relationships to disclose.