UGT1A1 GENOTYPES AND GLUCURONIDATION OF SN-38, THE ACTIVE METABOLITE OF IRINOTECAN

Background. Irinotecan (CPT-11) is metabolized by esterase to form a S N-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activi ty, We investigated whether there might be an inter-individual differe nce in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. Patients and methods: Nine male patients with lu ng cancer were treated with irinotecan (50 mg/m(2)) and carboplatin. P harmacokinetic parameters were calculated with full sampling plasma da ta. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Results: The genotyping anal ysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA) (7)TAA allele (UGT1A128). The remaining seven patients were homozygot e for (TA)(6)TAA allele (6/6, wild type). The metabolic ratios (SN-38/ SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteris tically higher than those in the patients with other genotypes (6/6 an d 6/7). Biliary index was 6980 versus 2180 +/- 1110 (range 840-3730) i n patients with 7/7 versus 6/6 genotypes, respectively. Conclusion: Th ese results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.