UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan

Background: Irinotecan (CPT-11) is metabolized by esterase to form a SN- 38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. Patients and methods: Nine male patients with lung cancer were treated with irinotecan (50 mg/m²) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Results: The genotyping analysis revealed one heterozygote (6/7) adn one homozygote (7/7) for (TA)₇TAA allele (UGT1A1* 28). The remaining seven patients were homozygote for (TA)₆TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 ± 1110 (range 840-3730) in patients with 7/7 versus 6/6 genotypes, respectively. Conclusion: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.