1. ¹Department of Pharmacy, Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
2. ²Department of Haematology-Oncology, National University Hospital, Singapore
3. ³Department of Pharmacy, Faculty of Science, School of Life Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Correspondence: Dr B Chowbay, Department of Pharmacy, Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610. E-mail: ctebal@nccs.com.sg

Received 8 April 2007; Revised 4 June 2007; Accepted 28 June 2007; Published online 14 August 2007.

Abstract

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.- 3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.- 118(T)_9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m² once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1–1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT₁₀T/GG6GT₉C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT₁₀T/GG6GT₁₀C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.